Neurobiology of Disease Molecular Cross Talk between Misfolded Proteins in Animal Models of Alzheimer's and Prion Diseases
Rodrigo Morales,1,2,3 Lisbell D. Estrada,2,3 Rodrigo Diaz-Espinoza,1,2 Diego Morales-Scheihing,1 Maria C. Jara,1 Joaquin Castilla,2 and Claudio Soto1,2
1Protein Misfolding Disorders Laboratory, Department of Neurology, Mitchell Center for Alzheimer's Disease and Related Brain Disorders, University of Texas Medical School at Houston, Houston, Texas 77030, 2Protein Misfolding Disorders Laboratory, Department of Neurology, University of Texas Medical Branch, Galveston, Texas 77555, and 3Facultad de Ciencias, Universidad de Chile, Santiago, Chile
Correspondence should be addressed to Claudio Soto at the above address. Email: claudio.soto@uth.tmc.edu
The central event in protein misfolding disorders (PMDs) is the accumulation of a misfolded form of a naturally expressed protein. Despite the diversity of clinical symptoms associated with different PMDs, many similarities in their mechanism suggest that distinct pathologies may cross talk at the molecular level. The main goal of this study was to analyze the interaction of the protein misfolding processes implicated in Alzheimer's and prion diseases. For this purpose, we inoculated prions in an Alzheimer's transgenic mouse model that develop typical amyloid plaques and followed the progression of pathological changes over time. Our findings show a dramatic acceleration and exacerbation of both pathologies. The onset of prion disease symptoms in transgenic mice appeared significantly faster with a concomitant increase on the level of misfolded prion protein in the brain. A striking increase in amyloid plaque deposition was observed in prion-infected mice compared with their noninoculated counterparts. Histological and biochemical studies showed the association of the two misfolded proteins in the brain and in vitro experiments showed that protein misfolding can be enhanced by a cross-seeding mechanism. These results suggest a profound interaction between Alzheimer's and prion pathologies, indicating that one protein misfolding process may be an important risk factor for the development of a second one. Our findings may have important implications to understand the origin and progression of PMDs.
-------------------------------------------------------------------------------- Received Nov. 30, 2009; revised Jan. 22, 2010; accepted Feb. 2, 2010.
Correspondence should be addressed to Claudio Soto at the above address. Email: claudio.soto@uth.tmc.edu
http://www.jneurosci.org/cgi/content/abstract/30/13/4528?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1&FIRSTINDEX=0&volume=30&issue=13&resourcetype=HWCIT
BSE101/1 0136
IN CONFIDENCE
CMO
From: Dr J S Metters DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognised the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.
2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed", As the report emphasises the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible.
What are the implications for public health?
3. The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process, Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.
92/11.4/1.1
4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.
J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832
92/11.4/1.2
http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
From: Dr. A Wight
Date: 5 January 1993
Copies:
Dr Metters
Dr Skinner
Dr Pickles
Dr Morris
Mr Murray
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of B amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
93/01.05/4.1
http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Friday, March 5, 2010
Fatal Transmissible Amyloid Encephalopathy: A New Type of Prion Disease Associated with Lack of Prion Protein Membrane Anchoring
http://betaamyloidcjd.blogspot.com/2010/03/fatal-transmissible-amyloid.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
TSS
Wednesday, March 31, 2010
Friday, March 5, 2010
Fatal Transmissible Amyloid Encephalopathy: A New Type of Prion Disease Associated with Lack of Prion Protein Membrane Anchoring
Fatal Transmissible Amyloid Encephalopathy: A New Type of Prion Disease Associated with Lack of Prion Protein Membrane Anchoring
Bruce Chesebro1*, Brent Race1, Kimberly Meade-White1, Rachel LaCasse1, Richard Race1, Mikael Klingeborn1, James Striebel1, David Dorward2, Gillian McGovern3, Martin Jeffrey3
1 Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana, United States of America, 2 Electron Microscopy Section, Research Technology Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana, United States of America, 3 VLA (Lasswade), Penicuik, Scotland, United Kingdom
Abstract
Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres). PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen), a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI). Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease.
Author Summary
Prion diseases, also known as transmissible spongiform encephalopathies, are infectious fatal neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated form which may contribute to brain damage. In uninfected individuals, normal PrP is anchored to the outer cell membrane by a sugar-phosphate-lipid linker molecule. In the present report we show that prion infection of mice expressing PrP lacking the anchor can result in a new type of fatal neurodegenerative disease. This disease displays mechanisms of damage to brain cells and brain blood vessels found in Alzheimer's disease and in familial amyloid brain diseases. In contrast, the typical sponge-like brain damage seen in prion diseases was not observed. These results suggest that presence or absence of PrP membrane anchoring can influence the type of neurodegeneration seen after prion infection.
Citation: Chesebro B, Race B, Meade-White K, LaCasse R, Race R, et al. (2010) Fatal Transmissible Amyloid Encephalopathy: A New Type of Prion Disease Associated with Lack of Prion Protein Membrane Anchoring. PLoS Pathog 6(3): e1000800. doi:10.1371/journal.ppat.1000800
Editor: David Westaway, University of Alberta, Canada
Received: September 25, 2009; Accepted: January 29, 2010; Published: March 5, 2010
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Funding: Funded by the Intramural program of NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: bchesebro@nih.gov
see full text here;
http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000800
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
TSS
Bruce Chesebro1*, Brent Race1, Kimberly Meade-White1, Rachel LaCasse1, Richard Race1, Mikael Klingeborn1, James Striebel1, David Dorward2, Gillian McGovern3, Martin Jeffrey3
1 Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana, United States of America, 2 Electron Microscopy Section, Research Technology Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana, United States of America, 3 VLA (Lasswade), Penicuik, Scotland, United Kingdom
Abstract
Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres). PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen), a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI). Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease.
Author Summary
Prion diseases, also known as transmissible spongiform encephalopathies, are infectious fatal neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated form which may contribute to brain damage. In uninfected individuals, normal PrP is anchored to the outer cell membrane by a sugar-phosphate-lipid linker molecule. In the present report we show that prion infection of mice expressing PrP lacking the anchor can result in a new type of fatal neurodegenerative disease. This disease displays mechanisms of damage to brain cells and brain blood vessels found in Alzheimer's disease and in familial amyloid brain diseases. In contrast, the typical sponge-like brain damage seen in prion diseases was not observed. These results suggest that presence or absence of PrP membrane anchoring can influence the type of neurodegeneration seen after prion infection.
Citation: Chesebro B, Race B, Meade-White K, LaCasse R, Race R, et al. (2010) Fatal Transmissible Amyloid Encephalopathy: A New Type of Prion Disease Associated with Lack of Prion Protein Membrane Anchoring. PLoS Pathog 6(3): e1000800. doi:10.1371/journal.ppat.1000800
Editor: David Westaway, University of Alberta, Canada
Received: September 25, 2009; Accepted: January 29, 2010; Published: March 5, 2010
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Funding: Funded by the Intramural program of NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: bchesebro@nih.gov
see full text here;
http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000800
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
TSS
Monday, January 4, 2010
Rising Tide: The Impact of Dementia in Canada
Huge wave of dementia cases coming, warns report
CTV.ca News Staff
Date: Mon. Jan. 4 2010 9:52 AM ET
So many Canadians are expected to develop Alzheimer's disease and dementia in the next 30 years that a new case will be diagnosed every two minutes unless preventive measures are taken, a new report says.
The report, released Monday by the Alzheimer Society, says the prevalence of dementia will more than double in the next 30 years.
By 2038, almost three per cent of Canada's population will be affected by dementia, and about 257,800 new cases will be diagnosed per year.
Today, dementia costs Canada about $15 billion a year; those costs could soon increase by 10-fold.
"If nothing changes, this sharp increase in the number of people living with dementia will mean that by 2038, the total costs associated with dementia will reach $153 billion a year," David Harvey, principal spokesperson for the Alzheimer Society project called "Rising Tide: The Impact of Dementia on Canadian Society," said in a statement.
That amounts to a cumulative total of $872 billion over the 30-year period.
Much of the increase in cases can be attributed to the "greying" of Canada. With Canadians living longer and baby boomers aging, there is expected to be a spike in many chronic diseases that come with age, such as heart disease, arthritis and cancer.
But the expected rising rates of dementia are not just about demographics; poor lifestyles also play a role.
It's been well documented that regular physical and mental exercise can delay the onset of dementia, which includes Alzheimer's disease and other progressive diseases that destroy brain cells. For that reason, the report recommends that all Canadians over 65 without dementia increase their physical activity by 50 per cent.
"Prevention is where we need to be starting," Harvey told Canada AM.
"We know that healthy eating and active living are antidotes to dementia."
The "Rising Tide" report calls on government to fund more health promotion to remind Canadians of the benefits of a healthy lifestyle.
"This intervention would reduce the number of people diagnosed with dementia, resulting in a reduction in the pressure on long-term care facilities, community care services and informal caregivers," the report says.
Need for national strategy
Just as important, Harvey says, is the need for Canada's health care system to adapt to accommodate the projected rise in dementia cases.
"Dementia is one of the leading cases of disability amongst older people," Harvey said, noting that the flood of dementia expected in the next 30 years could overwhelm emergency rooms and hospitals.
His group's report calls for more support for informal caregivers -- generally, family members -- who tend to be the ones who care for patients with dementia in the early stages of the disease.
"There are services that can be put in place to support caregivers, and also economic and financial support for caregivers," he said.
By also providing caregivers with skill-building and support programs, caregivers struggling with the overwhelming emotional and financial hardships of providing care may feel better equipped to care for their loved one.
That could go far to delay admission of patients into long-term care facilities, thereby lessening the burden on the health care system.
The report also suggests assigning "system navigators" to each newly diagnosed dementia patient and their caregivers. These case managers would help families navigate the health system to find the right social services for their loved one depending on their stage of dementia.
--------------------------------------------------------------------------------
Some facts about dementia:
The symptoms of dementia include a gradual and continuing decline of memory, changes in judgment or reasoning, mood and behaviour, and an inability to perform familiar tasks. Dementia can strike adults at any age, but has traditionally been diagnosed in people over 65. However, symptoms start much earlier, and an increasing number of people are being diagnosed in their 50s and early 60s. Age is the number one risk factor for dementia Alzheimer's disease, the most common form of dementia, accounts for approximately 64 per cent of all dementias in Canada. Other related dementias include Vascular Dementia, Frontotemporal Dementia, Creutzfeldt-Jakob Disease and Lewy body Dementia. There is no known cure for dementia. However, some medications can delay progression of the disease. Researchers are confident that within five to seven years, there will be treatments that attack the disease process itself, not just the symptoms.
http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20100104/dementia_surge_100104/20100104?hub=Health
Report Summary Rising Tide: The Impact of Dementia in Canada In this section :
Read a summary of Rising Tide: The Impact of Dementia in Canada
Download Rising Tide: The Impact of Dementia in Canada Rising Tide: the Impact of Dementia on Canadian Society is the final report of an Alzheimer Society project funded by Pfizer Canada, Health Canada, Public Health Agency of Canada, Canadian Institutes of Health Research and Rx&D. The purpose of the report was to:
Estimate the health and economic burden of dementia in Canada over the next 30 years; Analyze the possible effects of intervention scenarios upon this burden; Demonstrate how the proposed interventions could affect the health and economic impacts of dementia in Canada; Review policy options; Make recommendations on how to address the issue. The Findings of Rising Tide1 Health Burden of Dementia for Canada: 2008-2038²
Incidence of Alzheimer's disease and related dementias in Canada: 2008 - 103,700 new cases per year (1 every 5 minutes) 2038 - 257,800 new cases per year (1 every 2 minutes) Prevalence of Alzheimer's disease and related dementias in Canada: 2008 - 480,600 people with dementia (1.5% of Canada's population) 2038 - 1,125,200 people with dementia (2.8% of Canada's population) View the prevalence of dementia by age graph
View the prevalence of dementia by sex graph
Hours of informal care provided annually for people with dementia in Canada 2008 - 231 million hours 2038 - 756 million hours Economic Consequences of Dementia for Canada: 2008-2038²
The Economic Burden of dementia doubles every decade, increasing from $15 billion in 2008 to a startling $153 billion in 2038.
Economic Burden of Dementia (in future dollars) 2008 - $15 billion 2018 - $37 billion 2028 - $75 billion 2038 - $153 billion
Cumulative Consequences of Dementia over a 30-year period
Cumulative data represents the combined total of either the economic costs of dementia per year, or the number of people developing dementia per year, each year between 2008 and 2038. By 2038, the cumulative incidence of dementia will be more than 5.5 million people³, with a cumulative economic cost of $872 billion² (2008 dollars).
Implications – What can Canada do? What Has Been Done Elsewhere
Across the globe, many countries are recognizing the urgent issue of dementia. Australia, Norway, the Netherlands, France, Scotland and the United Kingdom have recently developed specific plans or frameworks for dealing with dementia.
View Alzheimer Disease International's graphs correlating research effort with contributions to mortality and disability.
Intervention Opportunities
Recognizing the urgent need to start turning the tide of dementia, Rising Tide describes four potential intervention scenarios, backed by current evidence that could become critical factors in reducing the impact of dementia.
The report tested the impact of four potential intervention scenarios:
Increasing Physical Activity Delay Onset of Dementia Caregiver Training, Support System Navigation All showed the potential for dramatic reductions in economic impact over the next 30 years.
Note: Rising Tide was undertaken in order to alert the Canadian public and federal, provincial and territorial politicians of the need for policies and approaches to address the looming dementia crisis. In the reports, you will find four suggested interventions. They are not meant to be definitive but to serve as illustrations of how the base case can be used to inform and shape policy in this field. The 5 recommendations in the report were developed through a comprehensive process of consultations with subject experts and stakeholders. The underlying message is that we must act now and that change is possible.
Recommendations
Rising Tide also makes five recommendations that would make up the components of a comprehensive National Dementia Strategy. They include:
An accelerated investment in all areas of dementia research. A clear recognition of the important role played by informal caregivers. An increased recognition of the importance of prevention and early intervention. Greater integration of care and increased use of chronic disease prevention and management. A strengthening of Canada's dementia workforce.
Download a copy of Rising Tide: The Impact of Dementia on Canadian Society.
Endnotes
Rising Tide: Impact of Dementia on Canadian Society is a report based on a study conducted by RiskAnalytica, a leading firm in risk management. RiskAnalytica's Life at Risk® simulation platform was customized for the Rising Tide study based on the latest dementia and health economic research, validated for epidemiological and economic aspects by subject matter experts and checked for data, logic and results. The simulation platform was then run to establish the Base Case, or the findings. Rising Tide: The Impact of Dementia on Canadian Society. Alzheimer Society, 2009. Smetanin, P., Kobak, P., Briante, C., Stiff, D., Sherman, G., and Ahmad, S. Rising Tide: The Impact of Dementia in Canada 2008 to 2038. RiskAnalytica, 2009.
http://www.alzheimer.ca/english/rising_tide/rising_tide_summary.htm
http://www.alzheimer.ca/english/rising_tide/rising_tide_report.htm
SEE FULL REPORT HERE ;
Rising Tide:
The Impact of Dementia on Canadian Society
Executive Summary
http://www.alzheimer.ca/docs/RisingTide/AS%20Rising%20Tide-Executive%20Summary_Eng_FINAL_SecuredVersion.pdf
Saturday, October 31, 2009
Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients
http://betaamyloidcjd.blogspot.com/2009/10/involvement-of-dab1-in-app-processing.html
SEAC OCTOBER 2009
. Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
http://www.seac.gov.uk/pdf/hol-response091008.pdf
Thursday, February 26, 2009
'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
93/01.05/4.1tss
http://web.archive.org/web/20010305223440/www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
http://web.archive.org/web/20010305222847/www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
snip...
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...
snip...
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf
And NONE of this is relevant to BSE?
There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992
CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://web.archive.org/web/20010305223143/www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
also, see the increase of Alzheimer's from 1981 to 1986
http://web.archive.org/web/20010305222847/www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
see full text ;
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
Saturday, October 31, 2009
Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients Copyright © 2009 Published by Elsevier Inc.
http://betaamyloidcjd.blogspot.com/2009/10/involvement-of-dab1-in-app-processing.html
----- Original Message -----
From: "Terry S. Singeltary Sr." To: Sent: Monday, October 12, 2009 9:47 AM Subject: [BSE-L] SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens Transmissible Spongiform Encephalopathy
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
snip...
. More specific examples of unanswered questions with health implications are:
. Will the eventual elimination of classical scrapie in the EU leave an ecological niche for other TSEs such as BSE or atypical scrapie?
. Is CWD transmissible to humans?
. Can a reliable ante mortem diagnostic blood test for vCJD be developed?
. What is the true prevalence of v CJD infection (as opposed to overt disease) in the UK?
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
--------------------------------------------------------------------------------
. Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
--------------------------------------------------------------------------------
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
. Could cases of protease sensitive prionopathy (PSP) be missed by conventional tests which, in all other TSEs, rely on the resistance of the prion protein in the nervous system that accompanies disease to digestion by protease enzymes?
. Can we develop reliable methods for removing and detecting protein on re-usable surgical instruments?
SNIP...
FULL TEXT ;
Monday, October 12, 2009
SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Sent: Monday, June 29, 2009 2:08 PM
Subject: [BSE-L] Beyond the prion principle
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
News and Views Nature 459, 924-925 (18 June 2009) doi:10.1038/459924a; Published online 17 June 2009
CELL BIOLOGY
Beyond the prion principle
Adriano Aguzzi
It seems that many misfolded proteins can act like prions - spreading disease by imparting their misshapen structure to normal cellular counterparts. But how common are bona fide prions really?
The protein-only hypothesis of prion propagation is steadily gaining ground. First envisaged by John Stanley Griffith1 and later formalized by Stanley Prusiner2, this theory proposes the existence of an infectious agent composed solely of protein. Three reports, two in Nature Cell Biology3,4 and one in The Journal of Cell Biology5, now contend that, far from being confined to the rare prion diseases, prion-like transmission of altered proteins may occur in several human diseases of the brain and other organs.
Prions are now accepted as causing the transmissible spongiform encephalopathies, which include scrapie in sheep, bovine spongiform encephalopathy (BSE, or mad cow disease) and its human variant Creutzfeldt-Jakob disease. The infectious prion particle is made up of PrPSc, a misfolded and aggregated version of a normal protein known as PrPC. Like the growth of crystals, PrPSc propagates by recruiting monomeric PrPC into its aggregates - a process that has been replicated in vitro6 and in transgenic mice7. The breakage of PrPSc aggregates represents the actual replicative event, as it multiplies the number of active seeds8.
Apart from prion diseases, the misfolding and aggregation of proteins into various harmful forms, which are collectively known as amyloid, causes a range of diseases of the nervous system and other organs. The clinical characteristics of amyloidoses, however, gave little reason to suspect a relationship to prion diseases. Hints of prion-like behaviour in amyloid have emerged from studies of Alzheimer's disease and Parkinson's disease. Alzheimer's disease had been suspected to be transmissible for some time: an early report9 of disease transmission to hamsters through white blood cells from people with Alzheimer's disease caused great consternation, but was never reproduced. Much more tantalizing evidence came from the discovery10,11 that aggregates of the amyloid-â (Aâ) peptide found in the brain of people with Alzheimer's disease could be transmitted to the brain of mice engineered to produce large amounts of the Aâ precursor protein APP. Another study12 has shown that healthy tissue grafted into the brain of people with Parkinson's disease acquires intracellular Lewy bodies - aggregates of the Parkinson's disease-associated protein á-synuclein. This suggests prion-like transmission of diseased protein from the recipient's brain to the grafted cells.
These findings10-12 raise a provocative question. If protein aggregation depends on the introduction of 'seeds' and on the availability of the monomeric precursor, and if, as has been suggested13, amyloid represents the primordial state of all proteins, wouldn't all proteins - under appropriate conditions - behave like prions in the presence of sufficient precursor? Acceptance of this concept is gaining momentum. For one thing, an increasing wealth of traits is being found in yeast, fungi and bacteria that can best be explained as prion-like phenomena (see table). And now, Ren and colleagues3 provide evidence for prion-like spread of polyglutamine (polyQ)- containing protein aggregates, which are similar to the aggregates found in Huntington's disease. They show that polyQ aggregates can be taken up from the outside by mammalian cells. Once in the cytosol, the polyQ aggregates can grow by recruiting endogenous polyQ. Clavaguera et al.4 report similar findings in a mouse model of tauopathy, a neurodegenerative disease caused by intraneuronal aggregation of the microtubule-associated tau protein. Injection of mutant human tau into the brain of mice overexpressing normal human tau transmitted tauopathy, with intracellular aggregation of previously normal tau and spread of aggregates to neighbouring regions of the brain. Notably, full-blown tauopathy was not induced in mice that did not express human tau. Assuming that tau pathology wasn't elicited by some indirect pathway (some mice overexpressing mutated human tau develop protein tangles even when exposed to un related amyloid aggregates14), this sequence of events is reminiscent of prions. Finally, Frost and colleagues5 show that extracellular tau aggregates can be taken up by cells in culture. Hence, tau can attack and penetrate cells from the outside, sporting predatory behaviour akin to that of prions.
Yet there is one crucial difference between actual prion diseases and diseases caused by other prion-like proteins (let's call them prionoids) described so far (see table). The behaviour of prions is entirely comparable to that of any other infectious agent: for instance, prions are transmissible between individuals and often across species, and can be assayed with classic microbiological techniques, including titration by bioassay. Accordingly, prion diseases were long thought to be caused by viruses, and BSE created a worldwide panic similar to that currently being provoked by influenza. By contrast, although prionoids can 'infect' neighbouring molecules and sometimes even neighbouring cells, they do not spread within communities or cause epidemics such as those seen with BSE.
So, should any amyloid deserve an upgrade to a bone fide prion status? Currently, amyloid A (AA) amyloidosis may be the most promising candidate for a truly infectious disease caused by a self-propagating protein other than PrPSc. AA amyloid consists of orderly aggregated fragments of the SAA protein, and its deposition damages many organs of the body. Seeds of AA amyloid can be excreted in faeces15, and can induce amyloidosis if taken up orally (at least in geese)16. Also, AA amyloid may be transmitted between mice by transfusion of white blood cells17. So, like entero viruses and, perhaps, sheep scrapie prions, AA amyloid seems to display all the elements of a complete infectious life cycle, including uptake, replication and release from its host.
There are intriguing evolutionary implications to the above findings. If prionoids are ubiquitous, why didn't evolution erect barriers to their pervasiveness? Maybe it is because the molecular transmissibility of aggregated states can sometimes be useful. Indeed, aggregation of the Sup35 protein, which leads to a prion-like phenomenon in yeast, may promote evolutionary adaptation by allowing yeast cells to temporarily activate DNA sequences that are normally untranslated18. Mammals have developed receptors for aggregates, and ironically PrPC may be one of them19, although these receptors have not been reported to mediate protective functions. Therefore, we shouldn't be shocked if instances of beneficial prionoids emerge in mammals as well. ¦
Adriano Aguzzi is at the Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland. e-mail: adriano.aguzzi@usz.ch
1. Griffith, J. S. Nature 215, 1043-1044 (1967). 2. Prusiner, S. B. Science 216, 136-144 (1982). 3. Ren, P.-H. et al. Nature Cell Biol. 11, 219-225 (2009). 4. Clavaguera, F. et al. Nature Cell Biol. doi:10.1038/ncb1901 (2009). 5. Frost, B., Jacks, R. L. & Diamond, M. I. J. Biol. Chem. 284, 12845-12852 (2009). 6. Castilla, J., Saá, P., Hetz, C. & Soto, C. Cell 121, 195-206 (2005). 7. Sigurdson, C. J. et al. Proc. Natl Acad. Sci. USA 106, 304-309 (2009). 8. Aguzzi, A. & Polymenidou, M. Cell 116, 313-327 (2004). 9. Manuelidis, E. E. et al. Proc. Natl Acad. Sci. USA 85, 4898-4901 (1988). 10. Kane, M. D. et al. J. Neurosci. 20, 3606-3611 (2000). 11. Meyer-Luehmann, M. et al. Science 313, 1781-1784 (2006). 12. Li, J.-Y. et al. Nature Med. 14, 501-503 (2008). 13. Chiti, F. & Dobson, C. M. Annu. Rev. Biochem. 75, 333-366 (2006). 14. GÖtz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Science 293, 1491-1495 (2001). 15. Zhang, B. et al. Proc. Natl Acad. Sci. USA 105, 7263-7268 (2008). 16. Solomon, A. et al. Proc. Natl Acad. Sci. USA 104, 10998-11001 (2007). 17. Sponarova, J., NystrÖm, S. N. & Westermark, G. T. PLoS ONE 3, e3308 (2008). 18. True, H. L. & Lindquist, S. L. Nature 407, 477-483 (2000). 19. Laurén, J. et al. Nature 457, 1128-1132 (2009).
PRIONS AND POTENTIAL PRIONOIDS
Disease Protein Molecular transmissibility Infectious life cycle Prion diseases PrPSc Yes Yes Alzheimer's disease Amyloid-ß Yes Not shown Tauopathies Tau Yes Not shown Parkinson's disease a-Synuclein Host-to-graft Not shown AA amyloidosis Amyloid A Yes Possible Huntington's disease Polyglutamine Yes Not shown Phenotype Protein Molecular transmissibility Infectious life cycle Suppressed translational termination (yeast) Sup35 Yes Not shown Heterokaryon incompatibility (filamentous fungi) Het-s Yes Not shown Biofilm promotion (bacteria) CsgA Yes Not shown In humans and animals, infectious prion diseases are caused by PrPSc, which spreads by recruiting its monomeric precursor PrPC into aggregates. Aggregates then multiply by breakage, a process that is termed molecular transmissibility. Other proteins involved in disease and in phenotypes of fungi and bacteria, can also undergo self-sustaining aggregation, but none of these 'prionoid' proteins behaves like typical infectious agents, nor do any of them enact a complete infectious life cycle - with the possible exception of AA amyloid. Correction In the News & Views article "Immunology: Immunity's ancient arms" by Gary W. Litman and John P. Cannon (Nature 459, 784-786; 2009), the name of the fi rst author of the Nature paper under discussion was misspelt. The author's name is P. Guo, not Gou as published.
© 2009 Macmillan Publishers Limited. All rights reserved
http://www.nature.com/nature/journal/v459/n7249/full/459924a.html
http://betaamyloidcjd.blogspot.com/2009/10/involvement-of-dab1-in-app-processing.html
Thursday, February 26, 2009
'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Saturday, January 2, 2010
Human Prion Diseases in the United States January 1, 2010 ***FINAL***
http://prionunitusaupdate2008.blogspot.com/2010/01/human-prion-diseases-in-united-states.html
Friday, January 01, 2010
Human Prion Diseases in the United States PART 1
http://creutzfeldt-jakob-disease.blogspot.com/2010/01/human-prion-diseases-in-united-states.html
my comments to PLosone here ;
http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd&root=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd
TSS
CTV.ca News Staff
Date: Mon. Jan. 4 2010 9:52 AM ET
So many Canadians are expected to develop Alzheimer's disease and dementia in the next 30 years that a new case will be diagnosed every two minutes unless preventive measures are taken, a new report says.
The report, released Monday by the Alzheimer Society, says the prevalence of dementia will more than double in the next 30 years.
By 2038, almost three per cent of Canada's population will be affected by dementia, and about 257,800 new cases will be diagnosed per year.
Today, dementia costs Canada about $15 billion a year; those costs could soon increase by 10-fold.
"If nothing changes, this sharp increase in the number of people living with dementia will mean that by 2038, the total costs associated with dementia will reach $153 billion a year," David Harvey, principal spokesperson for the Alzheimer Society project called "Rising Tide: The Impact of Dementia on Canadian Society," said in a statement.
That amounts to a cumulative total of $872 billion over the 30-year period.
Much of the increase in cases can be attributed to the "greying" of Canada. With Canadians living longer and baby boomers aging, there is expected to be a spike in many chronic diseases that come with age, such as heart disease, arthritis and cancer.
But the expected rising rates of dementia are not just about demographics; poor lifestyles also play a role.
It's been well documented that regular physical and mental exercise can delay the onset of dementia, which includes Alzheimer's disease and other progressive diseases that destroy brain cells. For that reason, the report recommends that all Canadians over 65 without dementia increase their physical activity by 50 per cent.
"Prevention is where we need to be starting," Harvey told Canada AM.
"We know that healthy eating and active living are antidotes to dementia."
The "Rising Tide" report calls on government to fund more health promotion to remind Canadians of the benefits of a healthy lifestyle.
"This intervention would reduce the number of people diagnosed with dementia, resulting in a reduction in the pressure on long-term care facilities, community care services and informal caregivers," the report says.
Need for national strategy
Just as important, Harvey says, is the need for Canada's health care system to adapt to accommodate the projected rise in dementia cases.
"Dementia is one of the leading cases of disability amongst older people," Harvey said, noting that the flood of dementia expected in the next 30 years could overwhelm emergency rooms and hospitals.
His group's report calls for more support for informal caregivers -- generally, family members -- who tend to be the ones who care for patients with dementia in the early stages of the disease.
"There are services that can be put in place to support caregivers, and also economic and financial support for caregivers," he said.
By also providing caregivers with skill-building and support programs, caregivers struggling with the overwhelming emotional and financial hardships of providing care may feel better equipped to care for their loved one.
That could go far to delay admission of patients into long-term care facilities, thereby lessening the burden on the health care system.
The report also suggests assigning "system navigators" to each newly diagnosed dementia patient and their caregivers. These case managers would help families navigate the health system to find the right social services for their loved one depending on their stage of dementia.
--------------------------------------------------------------------------------
Some facts about dementia:
The symptoms of dementia include a gradual and continuing decline of memory, changes in judgment or reasoning, mood and behaviour, and an inability to perform familiar tasks. Dementia can strike adults at any age, but has traditionally been diagnosed in people over 65. However, symptoms start much earlier, and an increasing number of people are being diagnosed in their 50s and early 60s. Age is the number one risk factor for dementia Alzheimer's disease, the most common form of dementia, accounts for approximately 64 per cent of all dementias in Canada. Other related dementias include Vascular Dementia, Frontotemporal Dementia, Creutzfeldt-Jakob Disease and Lewy body Dementia. There is no known cure for dementia. However, some medications can delay progression of the disease. Researchers are confident that within five to seven years, there will be treatments that attack the disease process itself, not just the symptoms.
http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20100104/dementia_surge_100104/20100104?hub=Health
Report Summary Rising Tide: The Impact of Dementia in Canada In this section :
Read a summary of Rising Tide: The Impact of Dementia in Canada
Download Rising Tide: The Impact of Dementia in Canada Rising Tide: the Impact of Dementia on Canadian Society is the final report of an Alzheimer Society project funded by Pfizer Canada, Health Canada, Public Health Agency of Canada, Canadian Institutes of Health Research and Rx&D. The purpose of the report was to:
Estimate the health and economic burden of dementia in Canada over the next 30 years; Analyze the possible effects of intervention scenarios upon this burden; Demonstrate how the proposed interventions could affect the health and economic impacts of dementia in Canada; Review policy options; Make recommendations on how to address the issue. The Findings of Rising Tide1 Health Burden of Dementia for Canada: 2008-2038²
Incidence of Alzheimer's disease and related dementias in Canada: 2008 - 103,700 new cases per year (1 every 5 minutes) 2038 - 257,800 new cases per year (1 every 2 minutes) Prevalence of Alzheimer's disease and related dementias in Canada: 2008 - 480,600 people with dementia (1.5% of Canada's population) 2038 - 1,125,200 people with dementia (2.8% of Canada's population) View the prevalence of dementia by age graph
View the prevalence of dementia by sex graph
Hours of informal care provided annually for people with dementia in Canada 2008 - 231 million hours 2038 - 756 million hours Economic Consequences of Dementia for Canada: 2008-2038²
The Economic Burden of dementia doubles every decade, increasing from $15 billion in 2008 to a startling $153 billion in 2038.
Economic Burden of Dementia (in future dollars) 2008 - $15 billion 2018 - $37 billion 2028 - $75 billion 2038 - $153 billion
Cumulative Consequences of Dementia over a 30-year period
Cumulative data represents the combined total of either the economic costs of dementia per year, or the number of people developing dementia per year, each year between 2008 and 2038. By 2038, the cumulative incidence of dementia will be more than 5.5 million people³, with a cumulative economic cost of $872 billion² (2008 dollars).
Implications – What can Canada do? What Has Been Done Elsewhere
Across the globe, many countries are recognizing the urgent issue of dementia. Australia, Norway, the Netherlands, France, Scotland and the United Kingdom have recently developed specific plans or frameworks for dealing with dementia.
View Alzheimer Disease International's graphs correlating research effort with contributions to mortality and disability.
Intervention Opportunities
Recognizing the urgent need to start turning the tide of dementia, Rising Tide describes four potential intervention scenarios, backed by current evidence that could become critical factors in reducing the impact of dementia.
The report tested the impact of four potential intervention scenarios:
Increasing Physical Activity Delay Onset of Dementia Caregiver Training, Support System Navigation All showed the potential for dramatic reductions in economic impact over the next 30 years.
Note: Rising Tide was undertaken in order to alert the Canadian public and federal, provincial and territorial politicians of the need for policies and approaches to address the looming dementia crisis. In the reports, you will find four suggested interventions. They are not meant to be definitive but to serve as illustrations of how the base case can be used to inform and shape policy in this field. The 5 recommendations in the report were developed through a comprehensive process of consultations with subject experts and stakeholders. The underlying message is that we must act now and that change is possible.
Recommendations
Rising Tide also makes five recommendations that would make up the components of a comprehensive National Dementia Strategy. They include:
An accelerated investment in all areas of dementia research. A clear recognition of the important role played by informal caregivers. An increased recognition of the importance of prevention and early intervention. Greater integration of care and increased use of chronic disease prevention and management. A strengthening of Canada's dementia workforce.
Download a copy of Rising Tide: The Impact of Dementia on Canadian Society.
Endnotes
Rising Tide: Impact of Dementia on Canadian Society is a report based on a study conducted by RiskAnalytica, a leading firm in risk management. RiskAnalytica's Life at Risk® simulation platform was customized for the Rising Tide study based on the latest dementia and health economic research, validated for epidemiological and economic aspects by subject matter experts and checked for data, logic and results. The simulation platform was then run to establish the Base Case, or the findings. Rising Tide: The Impact of Dementia on Canadian Society. Alzheimer Society, 2009. Smetanin, P., Kobak, P., Briante, C., Stiff, D., Sherman, G., and Ahmad, S. Rising Tide: The Impact of Dementia in Canada 2008 to 2038. RiskAnalytica, 2009.
http://www.alzheimer.ca/english/rising_tide/rising_tide_summary.htm
http://www.alzheimer.ca/english/rising_tide/rising_tide_report.htm
SEE FULL REPORT HERE ;
Rising Tide:
The Impact of Dementia on Canadian Society
Executive Summary
http://www.alzheimer.ca/docs/RisingTide/AS%20Rising%20Tide-Executive%20Summary_Eng_FINAL_SecuredVersion.pdf
Saturday, October 31, 2009
Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients
http://betaamyloidcjd.blogspot.com/2009/10/involvement-of-dab1-in-app-processing.html
SEAC OCTOBER 2009
. Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
http://www.seac.gov.uk/pdf/hol-response091008.pdf
Thursday, February 26, 2009
'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
93/01.05/4.1tss
http://web.archive.org/web/20010305223440/www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
http://web.archive.org/web/20010305222847/www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
snip...
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...
snip...
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf
And NONE of this is relevant to BSE?
There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992
CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://web.archive.org/web/20010305223143/www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
also, see the increase of Alzheimer's from 1981 to 1986
http://web.archive.org/web/20010305222847/www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
see full text ;
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
Saturday, October 31, 2009
Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients Copyright © 2009 Published by Elsevier Inc.
http://betaamyloidcjd.blogspot.com/2009/10/involvement-of-dab1-in-app-processing.html
----- Original Message -----
From: "Terry S. Singeltary Sr." To: Sent: Monday, October 12, 2009 9:47 AM Subject: [BSE-L] SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens Transmissible Spongiform Encephalopathy
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
snip...
. More specific examples of unanswered questions with health implications are:
. Will the eventual elimination of classical scrapie in the EU leave an ecological niche for other TSEs such as BSE or atypical scrapie?
. Is CWD transmissible to humans?
. Can a reliable ante mortem diagnostic blood test for vCJD be developed?
. What is the true prevalence of v CJD infection (as opposed to overt disease) in the UK?
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
--------------------------------------------------------------------------------
. Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
--------------------------------------------------------------------------------
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
. Could cases of protease sensitive prionopathy (PSP) be missed by conventional tests which, in all other TSEs, rely on the resistance of the prion protein in the nervous system that accompanies disease to digestion by protease enzymes?
. Can we develop reliable methods for removing and detecting protein on re-usable surgical instruments?
SNIP...
FULL TEXT ;
Monday, October 12, 2009
SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Sent: Monday, June 29, 2009 2:08 PM
Subject: [BSE-L] Beyond the prion principle
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
News and Views Nature 459, 924-925 (18 June 2009) doi:10.1038/459924a; Published online 17 June 2009
CELL BIOLOGY
Beyond the prion principle
Adriano Aguzzi
It seems that many misfolded proteins can act like prions - spreading disease by imparting their misshapen structure to normal cellular counterparts. But how common are bona fide prions really?
The protein-only hypothesis of prion propagation is steadily gaining ground. First envisaged by John Stanley Griffith1 and later formalized by Stanley Prusiner2, this theory proposes the existence of an infectious agent composed solely of protein. Three reports, two in Nature Cell Biology3,4 and one in The Journal of Cell Biology5, now contend that, far from being confined to the rare prion diseases, prion-like transmission of altered proteins may occur in several human diseases of the brain and other organs.
Prions are now accepted as causing the transmissible spongiform encephalopathies, which include scrapie in sheep, bovine spongiform encephalopathy (BSE, or mad cow disease) and its human variant Creutzfeldt-Jakob disease. The infectious prion particle is made up of PrPSc, a misfolded and aggregated version of a normal protein known as PrPC. Like the growth of crystals, PrPSc propagates by recruiting monomeric PrPC into its aggregates - a process that has been replicated in vitro6 and in transgenic mice7. The breakage of PrPSc aggregates represents the actual replicative event, as it multiplies the number of active seeds8.
Apart from prion diseases, the misfolding and aggregation of proteins into various harmful forms, which are collectively known as amyloid, causes a range of diseases of the nervous system and other organs. The clinical characteristics of amyloidoses, however, gave little reason to suspect a relationship to prion diseases. Hints of prion-like behaviour in amyloid have emerged from studies of Alzheimer's disease and Parkinson's disease. Alzheimer's disease had been suspected to be transmissible for some time: an early report9 of disease transmission to hamsters through white blood cells from people with Alzheimer's disease caused great consternation, but was never reproduced. Much more tantalizing evidence came from the discovery10,11 that aggregates of the amyloid-â (Aâ) peptide found in the brain of people with Alzheimer's disease could be transmitted to the brain of mice engineered to produce large amounts of the Aâ precursor protein APP. Another study12 has shown that healthy tissue grafted into the brain of people with Parkinson's disease acquires intracellular Lewy bodies - aggregates of the Parkinson's disease-associated protein á-synuclein. This suggests prion-like transmission of diseased protein from the recipient's brain to the grafted cells.
These findings10-12 raise a provocative question. If protein aggregation depends on the introduction of 'seeds' and on the availability of the monomeric precursor, and if, as has been suggested13, amyloid represents the primordial state of all proteins, wouldn't all proteins - under appropriate conditions - behave like prions in the presence of sufficient precursor? Acceptance of this concept is gaining momentum. For one thing, an increasing wealth of traits is being found in yeast, fungi and bacteria that can best be explained as prion-like phenomena (see table). And now, Ren and colleagues3 provide evidence for prion-like spread of polyglutamine (polyQ)- containing protein aggregates, which are similar to the aggregates found in Huntington's disease. They show that polyQ aggregates can be taken up from the outside by mammalian cells. Once in the cytosol, the polyQ aggregates can grow by recruiting endogenous polyQ. Clavaguera et al.4 report similar findings in a mouse model of tauopathy, a neurodegenerative disease caused by intraneuronal aggregation of the microtubule-associated tau protein. Injection of mutant human tau into the brain of mice overexpressing normal human tau transmitted tauopathy, with intracellular aggregation of previously normal tau and spread of aggregates to neighbouring regions of the brain. Notably, full-blown tauopathy was not induced in mice that did not express human tau. Assuming that tau pathology wasn't elicited by some indirect pathway (some mice overexpressing mutated human tau develop protein tangles even when exposed to un related amyloid aggregates14), this sequence of events is reminiscent of prions. Finally, Frost and colleagues5 show that extracellular tau aggregates can be taken up by cells in culture. Hence, tau can attack and penetrate cells from the outside, sporting predatory behaviour akin to that of prions.
Yet there is one crucial difference between actual prion diseases and diseases caused by other prion-like proteins (let's call them prionoids) described so far (see table). The behaviour of prions is entirely comparable to that of any other infectious agent: for instance, prions are transmissible between individuals and often across species, and can be assayed with classic microbiological techniques, including titration by bioassay. Accordingly, prion diseases were long thought to be caused by viruses, and BSE created a worldwide panic similar to that currently being provoked by influenza. By contrast, although prionoids can 'infect' neighbouring molecules and sometimes even neighbouring cells, they do not spread within communities or cause epidemics such as those seen with BSE.
So, should any amyloid deserve an upgrade to a bone fide prion status? Currently, amyloid A (AA) amyloidosis may be the most promising candidate for a truly infectious disease caused by a self-propagating protein other than PrPSc. AA amyloid consists of orderly aggregated fragments of the SAA protein, and its deposition damages many organs of the body. Seeds of AA amyloid can be excreted in faeces15, and can induce amyloidosis if taken up orally (at least in geese)16. Also, AA amyloid may be transmitted between mice by transfusion of white blood cells17. So, like entero viruses and, perhaps, sheep scrapie prions, AA amyloid seems to display all the elements of a complete infectious life cycle, including uptake, replication and release from its host.
There are intriguing evolutionary implications to the above findings. If prionoids are ubiquitous, why didn't evolution erect barriers to their pervasiveness? Maybe it is because the molecular transmissibility of aggregated states can sometimes be useful. Indeed, aggregation of the Sup35 protein, which leads to a prion-like phenomenon in yeast, may promote evolutionary adaptation by allowing yeast cells to temporarily activate DNA sequences that are normally untranslated18. Mammals have developed receptors for aggregates, and ironically PrPC may be one of them19, although these receptors have not been reported to mediate protective functions. Therefore, we shouldn't be shocked if instances of beneficial prionoids emerge in mammals as well. ¦
Adriano Aguzzi is at the Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland. e-mail: adriano.aguzzi@usz.ch
1. Griffith, J. S. Nature 215, 1043-1044 (1967). 2. Prusiner, S. B. Science 216, 136-144 (1982). 3. Ren, P.-H. et al. Nature Cell Biol. 11, 219-225 (2009). 4. Clavaguera, F. et al. Nature Cell Biol. doi:10.1038/ncb1901 (2009). 5. Frost, B., Jacks, R. L. & Diamond, M. I. J. Biol. Chem. 284, 12845-12852 (2009). 6. Castilla, J., Saá, P., Hetz, C. & Soto, C. Cell 121, 195-206 (2005). 7. Sigurdson, C. J. et al. Proc. Natl Acad. Sci. USA 106, 304-309 (2009). 8. Aguzzi, A. & Polymenidou, M. Cell 116, 313-327 (2004). 9. Manuelidis, E. E. et al. Proc. Natl Acad. Sci. USA 85, 4898-4901 (1988). 10. Kane, M. D. et al. J. Neurosci. 20, 3606-3611 (2000). 11. Meyer-Luehmann, M. et al. Science 313, 1781-1784 (2006). 12. Li, J.-Y. et al. Nature Med. 14, 501-503 (2008). 13. Chiti, F. & Dobson, C. M. Annu. Rev. Biochem. 75, 333-366 (2006). 14. GÖtz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Science 293, 1491-1495 (2001). 15. Zhang, B. et al. Proc. Natl Acad. Sci. USA 105, 7263-7268 (2008). 16. Solomon, A. et al. Proc. Natl Acad. Sci. USA 104, 10998-11001 (2007). 17. Sponarova, J., NystrÖm, S. N. & Westermark, G. T. PLoS ONE 3, e3308 (2008). 18. True, H. L. & Lindquist, S. L. Nature 407, 477-483 (2000). 19. Laurén, J. et al. Nature 457, 1128-1132 (2009).
PRIONS AND POTENTIAL PRIONOIDS
Disease Protein Molecular transmissibility Infectious life cycle Prion diseases PrPSc Yes Yes Alzheimer's disease Amyloid-ß Yes Not shown Tauopathies Tau Yes Not shown Parkinson's disease a-Synuclein Host-to-graft Not shown AA amyloidosis Amyloid A Yes Possible Huntington's disease Polyglutamine Yes Not shown Phenotype Protein Molecular transmissibility Infectious life cycle Suppressed translational termination (yeast) Sup35 Yes Not shown Heterokaryon incompatibility (filamentous fungi) Het-s Yes Not shown Biofilm promotion (bacteria) CsgA Yes Not shown In humans and animals, infectious prion diseases are caused by PrPSc, which spreads by recruiting its monomeric precursor PrPC into aggregates. Aggregates then multiply by breakage, a process that is termed molecular transmissibility. Other proteins involved in disease and in phenotypes of fungi and bacteria, can also undergo self-sustaining aggregation, but none of these 'prionoid' proteins behaves like typical infectious agents, nor do any of them enact a complete infectious life cycle - with the possible exception of AA amyloid. Correction In the News & Views article "Immunology: Immunity's ancient arms" by Gary W. Litman and John P. Cannon (Nature 459, 784-786; 2009), the name of the fi rst author of the Nature paper under discussion was misspelt. The author's name is P. Guo, not Gou as published.
© 2009 Macmillan Publishers Limited. All rights reserved
http://www.nature.com/nature/journal/v459/n7249/full/459924a.html
http://betaamyloidcjd.blogspot.com/2009/10/involvement-of-dab1-in-app-processing.html
Thursday, February 26, 2009
'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Saturday, January 2, 2010
Human Prion Diseases in the United States January 1, 2010 ***FINAL***
http://prionunitusaupdate2008.blogspot.com/2010/01/human-prion-diseases-in-united-states.html
Friday, January 01, 2010
Human Prion Diseases in the United States PART 1
http://creutzfeldt-jakob-disease.blogspot.com/2010/01/human-prion-diseases-in-united-states.html
my comments to PLosone here ;
http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd&root=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd
TSS
Saturday, November 14, 2009
Codistribution of Amyloid ß Plaques and Spongiform Degeneration in Familial Creutzfeldt-Jakob Disease With the E200K-129M Haplotype
Vol. 66 No. 10, October 2009
Codistribution of Amyloid ß Plaques and Spongiform Degeneration in Familial Creutzfeldt-Jakob Disease With the E200K-129M Haplotype
Nupur Ghoshal, MD, PhD; Ignazio Cali, MS; Richard Justin Perrin, MD, PhD; S. Andrew Josephson, MD; Ning Sun, MD, PhD; Pierluigi Gambetti, MD; John Carl Morris, MD
Arch Neurol. 2009;66(10):1240-1246.
Background Dominantly inherited Creutzfeldt-Jakob disease (CJD) represents 5% to 15% of all CJD cases. The E200K mutation in the prion protein (PrP) gene (PRNP) is the most frequent cause of familial CJD. Coexistent amyloid ß (Aß) plaques have been reported in some transmissible spongiform encephalopathies but to date have not been reported in familial CJD with the E200K mutation.
Objective To characterize a family with CJD in which Aß plaques codistribute with spongiform degeneration.
Design Clinicopathologic and molecular study of a family with CJD with the E200K-129M haplotype.
Setting Alzheimer disease research center.
Participants Two generations of a family.
Main Outcome Measures Clinical, biochemical, and neuropathologic observations in 2 generations of a family.
Results In this kindred, 3 autopsied cases showed pathologic changes typical for the E200K-129M haplotype, including spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, 2 of these cases (ages 57 and 63 years) showed numerous Aß plaques codistributed with spongiform degeneration. APOE genotyping in 2 cases revealed that Aß plaques were present in the APOE 4 carrier but not in the APOE 4 noncarrier. Two additional cases exhibited incomplete penetrance, as they had no clinical evidence of CJD at death after age 80 years but had affected siblings and children.
Conclusions To our knowledge, this is the first description of Aß plaques in familial CJD with the E200K mutation. The codistribution of plaques and CJD-associated changes suggests that PrP plays a central role in Aß formation and that Aß pathology and prion disease likely in fluence each other. The kindred described herein provides support that PrPE200K may result in increased Aß deposition.
Author Affiliations: Department of Neurology and Alzheimer's Disease Research Center (Drs Ghoshal, Perrin, and Morris) and Division of Neuropathology, Department of Pathology and Immunology (Drs Perrin and Morris), Washington University School of Medicine, St Louis, Missouri; National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio (Mr Cali and Dr Gambetti); Department of Neurology, University of California, San Francisco (Dr Josephson); and DuPage Neurological Associates, Willowbrook, Illinois (Dr Sun).
http://archneur.ama-assn.org/cgi/content/short/66/10/1240
Saturday, October 31, 2009
Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients
http://betaamyloidcjd.blogspot.com/2009/10/involvement-of-dab1-in-app-processing.html
SEAC OCTOBER 2009
. Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
http://www.seac.gov.uk/pdf/hol-response091008.pdf
Thursday, February 26, 2009
'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
93/01.05/4.1tss
http://web.archive.org/web/20010305223440/www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
http://web.archive.org/web/20010305222847/www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
snip...
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...
snip...
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf
And NONE of this is relevant to BSE?
There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992
CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://web.archive.org/web/20010305223143/www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
also, see the increase of Alzheimer's from 1981 to 1986
http://web.archive.org/web/20010305222847/www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
see full text ;
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
Monday, October 12, 2009
SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
Sunday, August 10, 2008
A New Prionopathy OR more of the same old BSe and sporadic CJD
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/new-prionopathy-or-more-of-same-old-bse.html
TSS
Codistribution of Amyloid ß Plaques and Spongiform Degeneration in Familial Creutzfeldt-Jakob Disease With the E200K-129M Haplotype
Nupur Ghoshal, MD, PhD; Ignazio Cali, MS; Richard Justin Perrin, MD, PhD; S. Andrew Josephson, MD; Ning Sun, MD, PhD; Pierluigi Gambetti, MD; John Carl Morris, MD
Arch Neurol. 2009;66(10):1240-1246.
Background Dominantly inherited Creutzfeldt-Jakob disease (CJD) represents 5% to 15% of all CJD cases. The E200K mutation in the prion protein (PrP) gene (PRNP) is the most frequent cause of familial CJD. Coexistent amyloid ß (Aß) plaques have been reported in some transmissible spongiform encephalopathies but to date have not been reported in familial CJD with the E200K mutation.
Objective To characterize a family with CJD in which Aß plaques codistribute with spongiform degeneration.
Design Clinicopathologic and molecular study of a family with CJD with the E200K-129M haplotype.
Setting Alzheimer disease research center.
Participants Two generations of a family.
Main Outcome Measures Clinical, biochemical, and neuropathologic observations in 2 generations of a family.
Results In this kindred, 3 autopsied cases showed pathologic changes typical for the E200K-129M haplotype, including spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, 2 of these cases (ages 57 and 63 years) showed numerous Aß plaques codistributed with spongiform degeneration. APOE genotyping in 2 cases revealed that Aß plaques were present in the APOE 4 carrier but not in the APOE 4 noncarrier. Two additional cases exhibited incomplete penetrance, as they had no clinical evidence of CJD at death after age 80 years but had affected siblings and children.
Conclusions To our knowledge, this is the first description of Aß plaques in familial CJD with the E200K mutation. The codistribution of plaques and CJD-associated changes suggests that PrP plays a central role in Aß formation and that Aß pathology and prion disease likely in fluence each other. The kindred described herein provides support that PrPE200K may result in increased Aß deposition.
Author Affiliations: Department of Neurology and Alzheimer's Disease Research Center (Drs Ghoshal, Perrin, and Morris) and Division of Neuropathology, Department of Pathology and Immunology (Drs Perrin and Morris), Washington University School of Medicine, St Louis, Missouri; National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio (Mr Cali and Dr Gambetti); Department of Neurology, University of California, San Francisco (Dr Josephson); and DuPage Neurological Associates, Willowbrook, Illinois (Dr Sun).
http://archneur.ama-assn.org/cgi/content/short/66/10/1240
Saturday, October 31, 2009
Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients
http://betaamyloidcjd.blogspot.com/2009/10/involvement-of-dab1-in-app-processing.html
SEAC OCTOBER 2009
. Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
http://www.seac.gov.uk/pdf/hol-response091008.pdf
Thursday, February 26, 2009
'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
93/01.05/4.1tss
http://web.archive.org/web/20010305223440/www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
http://web.archive.org/web/20010305222847/www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
snip...
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...
snip...
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf
And NONE of this is relevant to BSE?
There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf
http://web.archive.org/web/20010305223234/www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992
CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://web.archive.org/web/20010305223143/www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
also, see the increase of Alzheimer's from 1981 to 1986
http://web.archive.org/web/20010305222847/www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
see full text ;
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
Monday, October 12, 2009
SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
Sunday, August 10, 2008
A New Prionopathy OR more of the same old BSe and sporadic CJD
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/new-prionopathy-or-more-of-same-old-bse.html
TSS
Saturday, October 31, 2009
Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients
Copyright © 2009 Published by Elsevier Inc.
Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients
References and further reading may be available for this article. To view references and further reading you must purchase this article.
R. Gavína, c, I. Ferrerb, c, , and J.A. del Ríoa, c, ,
aMolecular and Cellular Neurobiotechnology, Institute of Bioengineering of Catalonia and Department of Cell Biology, University of Barcelona, Baldiri Reixac 15-21, 08028 Barcelona, Spain
bInstitute of Neuropathology (INP), IDIBELL-Hospital Universitari de Bellvitge, Faculty of Medicine, University of Barcelona, 08907 Hospitalet de LLobregat, Barcelona, Spain
cCentro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
Received 27 March 2009; revised 5 October 2009; accepted 10 October 2009. Available online 21 October 2009.
Abstract Alzheimer's disease and prion pathologies (e.g., Creutzfeldt–Jakob disease (CJD)) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. Dab1 has been implicated in the regulation of amyloid precursor protein (APP), but a direct link between human prion diseases and Dab1/APP interactions has not been published. Here we examined this putative relationship in 17 cases of sporadic CJD (sCJD) post-mortem. Biochemical analyses of brain tissue revealed two groups, which also correlated with PrPsc types 1 and 2. One group with PrPsc type 1 showed increased Dab1 phosphorylation and lower ßCTF production with an absence of Aß deposition. The second sCJD group, which carried PrPsc type 2, showed lower levels of Dab1 phosphorylation and ßCTF production, and Aß deposition. Thus, the present observations suggest a correlation between Dab1 phosphorylation, Aß deposition and PrPsc type in sCJD.
Keywords: Prionopathies; Amyloid plaques; Alzheimer's disease; Dab1
Article Outline Introduction Patients and methods Cases PrP typing Codon 129 genotyping Immunoprecipitation and Western immunoblotting Densitometry and statistical processing Results Analysis of Dab1 phosphorylation revealed two groups of sCJD cases ßCTF production and Aß deposition in sCJD Correlation between codon 129 polymorphism with PrPsc type and Aß deposits in sCJD groups Discussion Acknowledgements References
Fig. 1. Patterns of PrPsc type 1 and type 2 (PK: proteinase K pre-treatment). Three examples of PrPsc processing are illustrated. Every sample is run in parallel with a negative control (lane 1), a typical case of PrPsc type 1 (lane 2), a typical case type 2 (lane 3) and the case problem (lane 4).
View Within Article
--------------------------------------------------------------------------------
Fig. 2. Example of Western blot determination of pDab1 (A and B) and total Dab1 protein levels (C and D) in sCJD cases. sCJD cases were categorized as described above. Protein samples from different groups of sCJD (first and second groups) are shown. (B) The densitometric results are shown. Each data item corresponding to a sCJD case is displayed in the histograms. In addition, the mean and SEM in each group is also shown. A significant increase in the pDab1/Dab1 ratio is observed in the first group of sCJD cases compared to the second sCJD group and controls. (C and D) Parallel determination of total Dab1 levels in the same sCJD protein samples. The increased phosphorylation of Dab1 in the first sCJD cases correlates with decreased levels of total protein. Each dot corresponds to a single case. Asterisks indicate significant differences between sCJD groups and controls in (B) and (D). p < 0.05; p < 0.01 (ANOVA test). View Within Article --------------------------------------------------------------------------------
Fig. 3. Example of Western blotting determination of ßCTF (A and B) in sCJD cases compared to controls. sCJD cases were categorized as described above. Decreased levels of ßCTF can be seen in the first sCJD group compared to controls. (B) Histograms showing the densitometric study as in Fig. 2. Each dot corresponds to a single case. Asterisks indicate significant differences between sCJD groups and controls. p < 0.05 (ANOVA test). View Within Article --------------------------------------------------------------------------------
Fig. 4. Double-Y graphs illustrating the densitometric results of pDab1/Dab1 ratio (left Y axis) and CTFß levels (blue right Y axis) for each case (X axis). Each dot/square corresponds to a single case. Values of pDab1/Dab1 (black squares) and CTFß (blue circles) have been linked with a line and the area (grey for pDab1/Dab1 and violet for CTFß) has been completed for each patient group. Notice the clear differences in the distribution of the grey and violet areas between the 1st and the 2nd group of sCJD cases and controls. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) View Within Article --------------------------------------------------------------------------------
Fig. 5. Low power photomicrographs illustrating examples of amyloid plaques in some of the sCJD cases used in the present study after Aß immunocytochemistry. (A) No plaques (score 0). (B) A few diffuse plaques (score +). (C) Many diffuse plaques, some neuritic plaques (score ++). See Results for details. Scale bar (A) = 500 µm pertains to (B) and (C). View Within Article --------------------------------------------------------------------------------
Table 1. Main clinical characteristics of sCJD and control cases in the present study. F: female; M: male; M: methionine; V: valine; PrP type: PrPsc type 1: lower band of glycosylated PrPsc of 21 kDa; type 2: lower band of glycosylated PrPsc of 10 kDa. Aß plaques: 0, no plaques; +, a few diffuse plaques; ++, many diffuse plaques and some neuritic plaques. View Within Article Corresponding authors. J.A. del Río is to be contacted at MCN lab Institute of Bioengineering of Catalonia Baldiri and Reixac 15-20, 08028 Barcelona, Spain. Fax: +34 934020183. I. Ferrer, Institut de Neuropatologia Servei Anatomia Patològica IDIBELL-Hospital Universitari de Bellvitge Facultat de Medicina Universitat de Barcelona Feixa LLarga sn, 08907 Hospitalet de LLobregat, Barcelona, Spain. Fax: +34 934035810.
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WNK-4XH5MGD-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=77549367eefa411de83e198f26401bcc
TSS
----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Sent: Monday, October 12, 2009 9:47 AM
Subject: [BSE-L] SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens Transmissible Spongiform Encephalopathy
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
snip...
. More specific examples of unanswered questions with health implications are:
. Will the eventual elimination of classical scrapie in the EU leave an ecological niche for other TSEs such as BSE or atypical scrapie?
. Is CWD transmissible to humans?
. Can a reliable ante mortem diagnostic blood test for vCJD be developed?
. What is the true prevalence of v CJD infection (as opposed to overt disease) in the UK?
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
--------------------------------------------------------------------------------
. Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
--------------------------------------------------------------------------------
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
. Could cases of protease sensitive prionopathy (PSP) be missed by conventional tests which, in all other TSEs, rely on the resistance of the prion protein in the nervous system that accompanies disease to digestion by protease enzymes?
. Can we develop reliable methods for removing and detecting protein on re-usable surgical instruments?
SNIP...
FULL TEXT ;
Monday, October 12, 2009
SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Sent: Monday, June 29, 2009 2:08 PM
Subject: [BSE-L] Beyond the prion principle
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
News and Views Nature 459, 924-925 (18 June 2009) doi:10.1038/459924a; Published online 17 June 2009
CELL BIOLOGY
Beyond the prion principle
Adriano Aguzzi
It seems that many misfolded proteins can act like prions - spreading disease by imparting their misshapen structure to normal cellular counterparts. But how common are bona fide prions really?
The protein-only hypothesis of prion propagation is steadily gaining ground. First envisaged by John Stanley Griffith1 and later formalized by Stanley Prusiner2, this theory proposes the existence of an infectious agent composed solely of protein. Three reports, two in Nature Cell Biology3,4 and one in The Journal of Cell Biology5, now contend that, far from being confined to the rare prion diseases, prion-like transmission of altered proteins may occur in several human diseases of the brain and other organs.
Prions are now accepted as causing the transmissible spongiform encephalopathies, which include scrapie in sheep, bovine spongiform encephalopathy (BSE, or mad cow disease) and its human variant Creutzfeldt-Jakob disease. The infectious prion particle is made up of PrPSc, a misfolded and aggregated version of a normal protein known as PrPC. Like the growth of crystals, PrPSc propagates by recruiting monomeric PrPC into its aggregates - a process that has been replicated in vitro6 and in transgenic mice7. The breakage of PrPSc aggregates represents the actual replicative event, as it multiplies the number of active seeds8.
Apart from prion diseases, the misfolding and aggregation of proteins into various harmful forms, which are collectively known as amyloid, causes a range of diseases of the nervous system and other organs. The clinical characteristics of amyloidoses, however, gave little reason to suspect a relationship to prion diseases. Hints of prion-like behaviour in amyloid have emerged from studies of Alzheimer's disease and Parkinson's disease. Alzheimer's disease had been suspected to be transmissible for some time: an early report9 of disease transmission to hamsters through white blood cells from people with Alzheimer's disease caused great consternation, but was never reproduced. Much more tantalizing evidence came from the discovery10,11 that aggregates of the amyloid-â (Aâ) peptide found in the brain of people with Alzheimer's disease could be transmitted to the brain of mice engineered to produce large amounts of the Aâ precursor protein APP. Another study12 has shown that healthy tissue grafted into the brain of people with Parkinson's disease acquires intracellular Lewy bodies - aggregates of the Parkinson's disease-associated protein á-synuclein. This suggests prion-like transmission of diseased protein from the recipient's brain to the grafted cells.
These findings10-12 raise a provocative question. If protein aggregation depends on the introduction of 'seeds' and on the availability of the monomeric precursor, and if, as has been suggested13, amyloid represents the primordial state of all proteins, wouldn't all proteins - under appropriate conditions - behave like prions in the presence of sufficient precursor? Acceptance of this concept is gaining momentum. For one thing, an increasing wealth of traits is being found in yeast, fungi and bacteria that can best be explained as prion-like phenomena (see table). And now, Ren and colleagues3 provide evidence for prion-like spread of polyglutamine (polyQ)- containing protein aggregates, which are similar to the aggregates found in Huntington's disease. They show that polyQ aggregates can be taken up from the outside by mammalian cells. Once in the cytosol, the polyQ aggregates can grow by recruiting endogenous polyQ. Clavaguera et al.4 report similar findings in a mouse model of tauopathy, a neurodegenerative disease caused by intraneuronal aggregation of the microtubule-associated tau protein. Injection of mutant human tau into the brain of mice overexpressing normal human tau transmitted tauopathy, with intracellular aggregation of previously normal tau and spread of aggregates to neighbouring regions of the brain. Notably, full-blown tauopathy was not induced in mice that did not express human tau. Assuming that tau pathology wasn't elicited by some indirect pathway (some mice overexpressing mutated human tau develop protein tangles even when exposed to un related amyloid aggregates14), this sequence of events is reminiscent of prions. Finally, Frost and colleagues5 show that extracellular tau aggregates can be taken up by cells in culture. Hence, tau can attack and penetrate cells from the outside, sporting predatory behaviour akin to that of prions.
Yet there is one crucial difference between actual prion diseases and diseases caused by other prion-like proteins (let's call them prionoids) described so far (see table). The behaviour of prions is entirely comparable to that of any other infectious agent: for instance, prions are transmissible between individuals and often across species, and can be assayed with classic microbiological techniques, including titration by bioassay. Accordingly, prion diseases were long thought to be caused by viruses, and BSE created a worldwide panic similar to that currently being provoked by influenza. By contrast, although prionoids can 'infect' neighbouring molecules and sometimes even neighbouring cells, they do not spread within communities or cause epidemics such as those seen with BSE.
So, should any amyloid deserve an upgrade to a bone fide prion status? Currently, amyloid A (AA) amyloidosis may be the most promising candidate for a truly infectious disease caused by a self-propagating protein other than PrPSc. AA amyloid consists of orderly aggregated fragments of the SAA protein, and its deposition damages many organs of the body. Seeds of AA amyloid can be excreted in faeces15, and can induce amyloidosis if taken up orally (at least in geese)16. Also, AA amyloid may be transmitted between mice by transfusion of white blood cells17. So, like entero viruses and, perhaps, sheep scrapie prions, AA amyloid seems to display all the elements of a complete infectious life cycle, including uptake, replication and release from its host.
There are intriguing evolutionary implications to the above findings. If prionoids are ubiquitous, why didn't evolution erect barriers to their pervasiveness? Maybe it is because the molecular transmissibility of aggregated states can sometimes be useful. Indeed, aggregation of the Sup35 protein, which leads to a prion-like phenomenon in yeast, may promote evolutionary adaptation by allowing yeast cells to temporarily activate DNA sequences that are normally untranslated18. Mammals have developed receptors for aggregates, and ironically PrPC may be one of them19, although these receptors have not been reported to mediate protective functions. Therefore, we shouldn't be shocked if instances of beneficial prionoids emerge in mammals as well. ¦
Adriano Aguzzi is at the Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland. e-mail: adriano.aguzzi@usz.ch
1. Griffith, J. S. Nature 215, 1043-1044 (1967). 2. Prusiner, S. B. Science 216, 136-144 (1982). 3. Ren, P.-H. et al. Nature Cell Biol. 11, 219-225 (2009). 4. Clavaguera, F. et al. Nature Cell Biol. doi:10.1038/ncb1901 (2009). 5. Frost, B., Jacks, R. L. & Diamond, M. I. J. Biol. Chem. 284, 12845-12852 (2009). 6. Castilla, J., Saá, P., Hetz, C. & Soto, C. Cell 121, 195-206 (2005). 7. Sigurdson, C. J. et al. Proc. Natl Acad. Sci. USA 106, 304-309 (2009). 8. Aguzzi, A. & Polymenidou, M. Cell 116, 313-327 (2004). 9. Manuelidis, E. E. et al. Proc. Natl Acad. Sci. USA 85, 4898-4901 (1988). 10. Kane, M. D. et al. J. Neurosci. 20, 3606-3611 (2000). 11. Meyer-Luehmann, M. et al. Science 313, 1781-1784 (2006). 12. Li, J.-Y. et al. Nature Med. 14, 501-503 (2008). 13. Chiti, F. & Dobson, C. M. Annu. Rev. Biochem. 75, 333-366 (2006). 14. GÖtz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Science 293, 1491-1495 (2001). 15. Zhang, B. et al. Proc. Natl Acad. Sci. USA 105, 7263-7268 (2008). 16. Solomon, A. et al. Proc. Natl Acad. Sci. USA 104, 10998-11001 (2007). 17. Sponarova, J., NystrÖm, S. N. & Westermark, G. T. PLoS ONE 3, e3308 (2008). 18. True, H. L. & Lindquist, S. L. Nature 407, 477-483 (2000). 19. Laurén, J. et al. Nature 457, 1128-1132 (2009).
PRIONS AND POTENTIAL PRIONOIDS
Disease Protein Molecular transmissibility Infectious life cycle Prion diseases PrPSc Yes Yes Alzheimer's disease Amyloid-ß Yes Not shown Tauopathies Tau Yes Not shown Parkinson's disease a-Synuclein Host-to-graft Not shown AA amyloidosis Amyloid A Yes Possible Huntington's disease Polyglutamine Yes Not shown Phenotype Protein Molecular transmissibility Infectious life cycle Suppressed translational termination (yeast) Sup35 Yes Not shown Heterokaryon incompatibility (filamentous fungi) Het-s Yes Not shown Biofilm promotion (bacteria) CsgA Yes Not shown In humans and animals, infectious prion diseases are caused by PrPSc, which spreads by recruiting its monomeric precursor PrPC into aggregates. Aggregates then multiply by breakage, a process that is termed molecular transmissibility. Other proteins involved in disease and in phenotypes of fungi and bacteria, can also undergo self-sustaining aggregation, but none of these 'prionoid' proteins behaves like typical infectious agents, nor do any of them enact a complete infectious life cycle - with the possible exception of AA amyloid. Correction In the News & Views article "Immunology: Immunity's ancient arms" by Gary W. Litman and John P. Cannon (Nature 459, 784-786; 2009), the name of the fi rst author of the Nature paper under discussion was misspelt. The author's name is P. Guo, not Gou as published.
© 2009 Macmillan Publishers Limited. All rights reserved
http://www.nature.com/nature/journal/v459/n7249/full/459924a.html
Thursday, February 26, 2009
'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
93/01.05/4.1tss
http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
snip...
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...
snip...
http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf
And NONE of this is relevant to BSE?
There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.
http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf
THE LINE TO TAKE.
http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992
CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
also, see the increase of Alzheimer's from 1981 to 1986
http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
Occasional PrP plaques are seen in cases of Alzheimer's Disease
snip...
full text;
http://www.bseinquiry.gov.uk/files/ws/s310.pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
see full text ;
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
MAD COW DISEASE, AND U.S. BEEF TRADE
MAD COW DISEASE, CJD, TSE, SOUND SCIENCE, COMMERCE, AND SELLING YOUR SOUL TO THE DEVIL
http://usdameatexport.blogspot.com/2009/10/mad-cow-disease-and-us-beef-trade.html
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA
Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients
References and further reading may be available for this article. To view references and further reading you must purchase this article.
R. Gavína, c, I. Ferrerb, c, , and J.A. del Ríoa, c, ,
aMolecular and Cellular Neurobiotechnology, Institute of Bioengineering of Catalonia and Department of Cell Biology, University of Barcelona, Baldiri Reixac 15-21, 08028 Barcelona, Spain
bInstitute of Neuropathology (INP), IDIBELL-Hospital Universitari de Bellvitge, Faculty of Medicine, University of Barcelona, 08907 Hospitalet de LLobregat, Barcelona, Spain
cCentro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
Received 27 March 2009; revised 5 October 2009; accepted 10 October 2009. Available online 21 October 2009.
Abstract Alzheimer's disease and prion pathologies (e.g., Creutzfeldt–Jakob disease (CJD)) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. Dab1 has been implicated in the regulation of amyloid precursor protein (APP), but a direct link between human prion diseases and Dab1/APP interactions has not been published. Here we examined this putative relationship in 17 cases of sporadic CJD (sCJD) post-mortem. Biochemical analyses of brain tissue revealed two groups, which also correlated with PrPsc types 1 and 2. One group with PrPsc type 1 showed increased Dab1 phosphorylation and lower ßCTF production with an absence of Aß deposition. The second sCJD group, which carried PrPsc type 2, showed lower levels of Dab1 phosphorylation and ßCTF production, and Aß deposition. Thus, the present observations suggest a correlation between Dab1 phosphorylation, Aß deposition and PrPsc type in sCJD.
Keywords: Prionopathies; Amyloid plaques; Alzheimer's disease; Dab1
Article Outline Introduction Patients and methods Cases PrP typing Codon 129 genotyping Immunoprecipitation and Western immunoblotting Densitometry and statistical processing Results Analysis of Dab1 phosphorylation revealed two groups of sCJD cases ßCTF production and Aß deposition in sCJD Correlation between codon 129 polymorphism with PrPsc type and Aß deposits in sCJD groups Discussion Acknowledgements References
Fig. 1. Patterns of PrPsc type 1 and type 2 (PK: proteinase K pre-treatment). Three examples of PrPsc processing are illustrated. Every sample is run in parallel with a negative control (lane 1), a typical case of PrPsc type 1 (lane 2), a typical case type 2 (lane 3) and the case problem (lane 4).
View Within Article
--------------------------------------------------------------------------------
Fig. 2. Example of Western blot determination of pDab1 (A and B) and total Dab1 protein levels (C and D) in sCJD cases. sCJD cases were categorized as described above. Protein samples from different groups of sCJD (first and second groups) are shown. (B) The densitometric results are shown. Each data item corresponding to a sCJD case is displayed in the histograms. In addition, the mean and SEM in each group is also shown. A significant increase in the pDab1/Dab1 ratio is observed in the first group of sCJD cases compared to the second sCJD group and controls. (C and D) Parallel determination of total Dab1 levels in the same sCJD protein samples. The increased phosphorylation of Dab1 in the first sCJD cases correlates with decreased levels of total protein. Each dot corresponds to a single case. Asterisks indicate significant differences between sCJD groups and controls in (B) and (D). p < 0.05; p < 0.01 (ANOVA test). View Within Article --------------------------------------------------------------------------------
Fig. 3. Example of Western blotting determination of ßCTF (A and B) in sCJD cases compared to controls. sCJD cases were categorized as described above. Decreased levels of ßCTF can be seen in the first sCJD group compared to controls. (B) Histograms showing the densitometric study as in Fig. 2. Each dot corresponds to a single case. Asterisks indicate significant differences between sCJD groups and controls. p < 0.05 (ANOVA test). View Within Article --------------------------------------------------------------------------------
Fig. 4. Double-Y graphs illustrating the densitometric results of pDab1/Dab1 ratio (left Y axis) and CTFß levels (blue right Y axis) for each case (X axis). Each dot/square corresponds to a single case. Values of pDab1/Dab1 (black squares) and CTFß (blue circles) have been linked with a line and the area (grey for pDab1/Dab1 and violet for CTFß) has been completed for each patient group. Notice the clear differences in the distribution of the grey and violet areas between the 1st and the 2nd group of sCJD cases and controls. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) View Within Article --------------------------------------------------------------------------------
Fig. 5. Low power photomicrographs illustrating examples of amyloid plaques in some of the sCJD cases used in the present study after Aß immunocytochemistry. (A) No plaques (score 0). (B) A few diffuse plaques (score +). (C) Many diffuse plaques, some neuritic plaques (score ++). See Results for details. Scale bar (A) = 500 µm pertains to (B) and (C). View Within Article --------------------------------------------------------------------------------
Table 1. Main clinical characteristics of sCJD and control cases in the present study. F: female; M: male; M: methionine; V: valine; PrP type: PrPsc type 1: lower band of glycosylated PrPsc of 21 kDa; type 2: lower band of glycosylated PrPsc of 10 kDa. Aß plaques: 0, no plaques; +, a few diffuse plaques; ++, many diffuse plaques and some neuritic plaques. View Within Article Corresponding authors. J.A. del Río is to be contacted at MCN lab Institute of Bioengineering of Catalonia Baldiri and Reixac 15-20, 08028 Barcelona, Spain. Fax: +34 934020183. I. Ferrer, Institut de Neuropatologia Servei Anatomia Patològica IDIBELL-Hospital Universitari de Bellvitge Facultat de Medicina Universitat de Barcelona Feixa LLarga sn, 08907 Hospitalet de LLobregat, Barcelona, Spain. Fax: +34 934035810.
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WNK-4XH5MGD-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=77549367eefa411de83e198f26401bcc
TSS
----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Sent: Monday, October 12, 2009 9:47 AM
Subject: [BSE-L] SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens Transmissible Spongiform Encephalopathy
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
snip...
. More specific examples of unanswered questions with health implications are:
. Will the eventual elimination of classical scrapie in the EU leave an ecological niche for other TSEs such as BSE or atypical scrapie?
. Is CWD transmissible to humans?
. Can a reliable ante mortem diagnostic blood test for vCJD be developed?
. What is the true prevalence of v CJD infection (as opposed to overt disease) in the UK?
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
--------------------------------------------------------------------------------
. Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility
--------------------------------------------------------------------------------
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
. Could cases of protease sensitive prionopathy (PSP) be missed by conventional tests which, in all other TSEs, rely on the resistance of the prion protein in the nervous system that accompanies disease to digestion by protease enzymes?
. Can we develop reliable methods for removing and detecting protein on re-usable surgical instruments?
SNIP...
FULL TEXT ;
Monday, October 12, 2009
SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Sent: Monday, June 29, 2009 2:08 PM
Subject: [BSE-L] Beyond the prion principle
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
News and Views Nature 459, 924-925 (18 June 2009) doi:10.1038/459924a; Published online 17 June 2009
CELL BIOLOGY
Beyond the prion principle
Adriano Aguzzi
It seems that many misfolded proteins can act like prions - spreading disease by imparting their misshapen structure to normal cellular counterparts. But how common are bona fide prions really?
The protein-only hypothesis of prion propagation is steadily gaining ground. First envisaged by John Stanley Griffith1 and later formalized by Stanley Prusiner2, this theory proposes the existence of an infectious agent composed solely of protein. Three reports, two in Nature Cell Biology3,4 and one in The Journal of Cell Biology5, now contend that, far from being confined to the rare prion diseases, prion-like transmission of altered proteins may occur in several human diseases of the brain and other organs.
Prions are now accepted as causing the transmissible spongiform encephalopathies, which include scrapie in sheep, bovine spongiform encephalopathy (BSE, or mad cow disease) and its human variant Creutzfeldt-Jakob disease. The infectious prion particle is made up of PrPSc, a misfolded and aggregated version of a normal protein known as PrPC. Like the growth of crystals, PrPSc propagates by recruiting monomeric PrPC into its aggregates - a process that has been replicated in vitro6 and in transgenic mice7. The breakage of PrPSc aggregates represents the actual replicative event, as it multiplies the number of active seeds8.
Apart from prion diseases, the misfolding and aggregation of proteins into various harmful forms, which are collectively known as amyloid, causes a range of diseases of the nervous system and other organs. The clinical characteristics of amyloidoses, however, gave little reason to suspect a relationship to prion diseases. Hints of prion-like behaviour in amyloid have emerged from studies of Alzheimer's disease and Parkinson's disease. Alzheimer's disease had been suspected to be transmissible for some time: an early report9 of disease transmission to hamsters through white blood cells from people with Alzheimer's disease caused great consternation, but was never reproduced. Much more tantalizing evidence came from the discovery10,11 that aggregates of the amyloid-â (Aâ) peptide found in the brain of people with Alzheimer's disease could be transmitted to the brain of mice engineered to produce large amounts of the Aâ precursor protein APP. Another study12 has shown that healthy tissue grafted into the brain of people with Parkinson's disease acquires intracellular Lewy bodies - aggregates of the Parkinson's disease-associated protein á-synuclein. This suggests prion-like transmission of diseased protein from the recipient's brain to the grafted cells.
These findings10-12 raise a provocative question. If protein aggregation depends on the introduction of 'seeds' and on the availability of the monomeric precursor, and if, as has been suggested13, amyloid represents the primordial state of all proteins, wouldn't all proteins - under appropriate conditions - behave like prions in the presence of sufficient precursor? Acceptance of this concept is gaining momentum. For one thing, an increasing wealth of traits is being found in yeast, fungi and bacteria that can best be explained as prion-like phenomena (see table). And now, Ren and colleagues3 provide evidence for prion-like spread of polyglutamine (polyQ)- containing protein aggregates, which are similar to the aggregates found in Huntington's disease. They show that polyQ aggregates can be taken up from the outside by mammalian cells. Once in the cytosol, the polyQ aggregates can grow by recruiting endogenous polyQ. Clavaguera et al.4 report similar findings in a mouse model of tauopathy, a neurodegenerative disease caused by intraneuronal aggregation of the microtubule-associated tau protein. Injection of mutant human tau into the brain of mice overexpressing normal human tau transmitted tauopathy, with intracellular aggregation of previously normal tau and spread of aggregates to neighbouring regions of the brain. Notably, full-blown tauopathy was not induced in mice that did not express human tau. Assuming that tau pathology wasn't elicited by some indirect pathway (some mice overexpressing mutated human tau develop protein tangles even when exposed to un related amyloid aggregates14), this sequence of events is reminiscent of prions. Finally, Frost and colleagues5 show that extracellular tau aggregates can be taken up by cells in culture. Hence, tau can attack and penetrate cells from the outside, sporting predatory behaviour akin to that of prions.
Yet there is one crucial difference between actual prion diseases and diseases caused by other prion-like proteins (let's call them prionoids) described so far (see table). The behaviour of prions is entirely comparable to that of any other infectious agent: for instance, prions are transmissible between individuals and often across species, and can be assayed with classic microbiological techniques, including titration by bioassay. Accordingly, prion diseases were long thought to be caused by viruses, and BSE created a worldwide panic similar to that currently being provoked by influenza. By contrast, although prionoids can 'infect' neighbouring molecules and sometimes even neighbouring cells, they do not spread within communities or cause epidemics such as those seen with BSE.
So, should any amyloid deserve an upgrade to a bone fide prion status? Currently, amyloid A (AA) amyloidosis may be the most promising candidate for a truly infectious disease caused by a self-propagating protein other than PrPSc. AA amyloid consists of orderly aggregated fragments of the SAA protein, and its deposition damages many organs of the body. Seeds of AA amyloid can be excreted in faeces15, and can induce amyloidosis if taken up orally (at least in geese)16. Also, AA amyloid may be transmitted between mice by transfusion of white blood cells17. So, like entero viruses and, perhaps, sheep scrapie prions, AA amyloid seems to display all the elements of a complete infectious life cycle, including uptake, replication and release from its host.
There are intriguing evolutionary implications to the above findings. If prionoids are ubiquitous, why didn't evolution erect barriers to their pervasiveness? Maybe it is because the molecular transmissibility of aggregated states can sometimes be useful. Indeed, aggregation of the Sup35 protein, which leads to a prion-like phenomenon in yeast, may promote evolutionary adaptation by allowing yeast cells to temporarily activate DNA sequences that are normally untranslated18. Mammals have developed receptors for aggregates, and ironically PrPC may be one of them19, although these receptors have not been reported to mediate protective functions. Therefore, we shouldn't be shocked if instances of beneficial prionoids emerge in mammals as well. ¦
Adriano Aguzzi is at the Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland. e-mail: adriano.aguzzi@usz.ch
1. Griffith, J. S. Nature 215, 1043-1044 (1967). 2. Prusiner, S. B. Science 216, 136-144 (1982). 3. Ren, P.-H. et al. Nature Cell Biol. 11, 219-225 (2009). 4. Clavaguera, F. et al. Nature Cell Biol. doi:10.1038/ncb1901 (2009). 5. Frost, B., Jacks, R. L. & Diamond, M. I. J. Biol. Chem. 284, 12845-12852 (2009). 6. Castilla, J., Saá, P., Hetz, C. & Soto, C. Cell 121, 195-206 (2005). 7. Sigurdson, C. J. et al. Proc. Natl Acad. Sci. USA 106, 304-309 (2009). 8. Aguzzi, A. & Polymenidou, M. Cell 116, 313-327 (2004). 9. Manuelidis, E. E. et al. Proc. Natl Acad. Sci. USA 85, 4898-4901 (1988). 10. Kane, M. D. et al. J. Neurosci. 20, 3606-3611 (2000). 11. Meyer-Luehmann, M. et al. Science 313, 1781-1784 (2006). 12. Li, J.-Y. et al. Nature Med. 14, 501-503 (2008). 13. Chiti, F. & Dobson, C. M. Annu. Rev. Biochem. 75, 333-366 (2006). 14. GÖtz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Science 293, 1491-1495 (2001). 15. Zhang, B. et al. Proc. Natl Acad. Sci. USA 105, 7263-7268 (2008). 16. Solomon, A. et al. Proc. Natl Acad. Sci. USA 104, 10998-11001 (2007). 17. Sponarova, J., NystrÖm, S. N. & Westermark, G. T. PLoS ONE 3, e3308 (2008). 18. True, H. L. & Lindquist, S. L. Nature 407, 477-483 (2000). 19. Laurén, J. et al. Nature 457, 1128-1132 (2009).
PRIONS AND POTENTIAL PRIONOIDS
Disease Protein Molecular transmissibility Infectious life cycle Prion diseases PrPSc Yes Yes Alzheimer's disease Amyloid-ß Yes Not shown Tauopathies Tau Yes Not shown Parkinson's disease a-Synuclein Host-to-graft Not shown AA amyloidosis Amyloid A Yes Possible Huntington's disease Polyglutamine Yes Not shown Phenotype Protein Molecular transmissibility Infectious life cycle Suppressed translational termination (yeast) Sup35 Yes Not shown Heterokaryon incompatibility (filamentous fungi) Het-s Yes Not shown Biofilm promotion (bacteria) CsgA Yes Not shown In humans and animals, infectious prion diseases are caused by PrPSc, which spreads by recruiting its monomeric precursor PrPC into aggregates. Aggregates then multiply by breakage, a process that is termed molecular transmissibility. Other proteins involved in disease and in phenotypes of fungi and bacteria, can also undergo self-sustaining aggregation, but none of these 'prionoid' proteins behaves like typical infectious agents, nor do any of them enact a complete infectious life cycle - with the possible exception of AA amyloid. Correction In the News & Views article "Immunology: Immunity's ancient arms" by Gary W. Litman and John P. Cannon (Nature 459, 784-786; 2009), the name of the fi rst author of the Nature paper under discussion was misspelt. The author's name is P. Guo, not Gou as published.
© 2009 Macmillan Publishers Limited. All rights reserved
http://www.nature.com/nature/journal/v459/n7249/full/459924a.html
Thursday, February 26, 2009
'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
93/01.05/4.1tss
http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
snip...
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...
snip...
http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf
And NONE of this is relevant to BSE?
There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.
http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf
THE LINE TO TAKE.
http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992
CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
also, see the increase of Alzheimer's from 1981 to 1986
http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
Occasional PrP plaques are seen in cases of Alzheimer's Disease
snip...
full text;
http://www.bseinquiry.gov.uk/files/ws/s310.pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
see full text ;
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
MAD COW DISEASE, AND U.S. BEEF TRADE
MAD COW DISEASE, CJD, TSE, SOUND SCIENCE, COMMERCE, AND SELLING YOUR SOUL TO THE DEVIL
http://usdameatexport.blogspot.com/2009/10/mad-cow-disease-and-us-beef-trade.html
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA
Monday, September 7, 2009
Scientists uncover new hereditary links to Alzheimer’s disease
Scientists uncover new hereditary links to Alzheimer’s disease
7 September 2009
Two genes which increase a person’s likelihood of developing the most common form of Alzheimer’s disease have been discovered in the largest-ever study of its kind into the illness. This international study, which received major funding from the Medical Research Council (MRC), is a significant step forward in understanding how Alzheimer’s develops and opens up new areas for further research into potential treatment and genetic screening.
Results from the research, which involved analysing the DNA from over 16,000 people over two years, show the genes CLU and PICALM can play a direct role in the risk of developing Alzheimer’s disease. Until now only one gene, APOE4, had been clearly identified as a potential risk factor. The Genome-Wide Association Study (GWAS) has emerged from the MRC new flagship research centre in Cardiff which is dedicated to genetic research into the disorders of the brain.
Lead author of the study, Professor Julie Williams, said:
“This research is changing our understanding of what might cause the common form of Alzheimer’s disease and could provide valuable new leads in the race to find treatments. If we can combat the detrimental effects of these two genes, we estimate it could reduce the chances of people developing Alzheimer's by almost 20%.”
Sir Leszek Borysiewicz, Chief Executive of the Medical Research Council, said: “Funding work on neurodegenerative diseases is priority for us and MRC investment in this kind of innovative research is crucial in piecing together the Alzheimer’s puzzle. This study is a huge step towards achieving an earlier diagnosis of Alzheimer’s and improving the lives of the many people affected by the disease."
Dr Marie Janson, Director of Development at the Alzheimer’s Research Trust, said:
“These unprecedented findings are the result of collaborations led by funders and scientists alike. Charities including the Alzheimer’s Research Trust and Wellcome Trust enhanced the MRC’s immense contribution to this work, while scientists throughout the UK and around the world shared data, ideas and more to make the study possible. This opens up multiple avenues that could lead to the development of new treatments for this devastating disease.”
The Medical Research Council invested £1.74 million in the programme of research, alongside major funding from the Wellcome Trust, the Welsh Assembly Government and the Alzheimer’s Research Trust, among others.
2
Data from the GWAS research was shared with a further French-led study, which has revealed compelling evidence for a third gene associated with Alzheimer’s called CR1.
Notes:
1. The Medical Research Council is dedicated to improving human health through excellent science. It invests on behalf of the UK taxpayer. Its work ranges from molecular level science to public health research, carried out in universities, hospitals and a network of its own units and institutes. The results have led to some of the most significant discoveries in medical science and benefited the health and wealth of millions of people in the UK and around the world. www.mrc.ac.uk
2. The Genome-Wide Association Study (GWAS) identifies variants at CLU and PICALM associated with Alzheimer’s disease’ by Williams et al is published in Nature Genetics.
3. Both CLU and PICALM highlight new pathways that lead to Alzheimer's disease. The CLU gene produces clusterin which normally acts to protect the brain in a variety of ways. Variation in this gene could remove this protection and contribute to Alzheimer's development. PICALM is important at synapses - connections between brain cells - and is involved in the transport of molecules into and inside of nerve cells, helping form memories and other brain functions. We know that the health of synapses is closely related to memory performance in Alzheimer's disease, thus changes in genes which affect synapses are likely to have a direct effect on disease development.
4. Professor Julie Williams is Professor of Neuropsychology Genetics at the Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics based at the University of Cardiff. For more information about the new flagship centre in Cardiff visit:
http://www.mrc.ac.uk/Newspublications/News/MRC006193
5. Alzheimer's disease is the most common cause of dementia, affecting around 417,000 people in the UK. Alzheimer's disease, first described by the German neurologist Alois Alzheimer, is a physical disease affecting the brain. During the course of the disease, 'plaques' and 'tangles' develop in the structure of the brain, leading to the death of brain cells. People with Alzheimer's also have a shortage of some important chemicals in their brains. These chemicals are involved with the transmission of messages within the brain
6. Following the establishment of a collaborative consortium between Europe and the United States, the investigation involved researchers from universities in Cardiff, London, Cambridge, Nottingham, Southampton, Manchester, Oxford, Bristol and Belfast, as well as Irish, German, Belgian, Greek and American institutions.
Press contact: 020 7637 6011
press.office@headoffice.mrc.ac.uk
http://www.mrc.ac.uk/consumption/groups/public/documents/content/mrc006341.pdf
SEE ALZHEIMER'S AND CJD
http://betaamyloidcjd.blogspot.com/
TSS
7 September 2009
Two genes which increase a person’s likelihood of developing the most common form of Alzheimer’s disease have been discovered in the largest-ever study of its kind into the illness. This international study, which received major funding from the Medical Research Council (MRC), is a significant step forward in understanding how Alzheimer’s develops and opens up new areas for further research into potential treatment and genetic screening.
Results from the research, which involved analysing the DNA from over 16,000 people over two years, show the genes CLU and PICALM can play a direct role in the risk of developing Alzheimer’s disease. Until now only one gene, APOE4, had been clearly identified as a potential risk factor. The Genome-Wide Association Study (GWAS) has emerged from the MRC new flagship research centre in Cardiff which is dedicated to genetic research into the disorders of the brain.
Lead author of the study, Professor Julie Williams, said:
“This research is changing our understanding of what might cause the common form of Alzheimer’s disease and could provide valuable new leads in the race to find treatments. If we can combat the detrimental effects of these two genes, we estimate it could reduce the chances of people developing Alzheimer's by almost 20%.”
Sir Leszek Borysiewicz, Chief Executive of the Medical Research Council, said: “Funding work on neurodegenerative diseases is priority for us and MRC investment in this kind of innovative research is crucial in piecing together the Alzheimer’s puzzle. This study is a huge step towards achieving an earlier diagnosis of Alzheimer’s and improving the lives of the many people affected by the disease."
Dr Marie Janson, Director of Development at the Alzheimer’s Research Trust, said:
“These unprecedented findings are the result of collaborations led by funders and scientists alike. Charities including the Alzheimer’s Research Trust and Wellcome Trust enhanced the MRC’s immense contribution to this work, while scientists throughout the UK and around the world shared data, ideas and more to make the study possible. This opens up multiple avenues that could lead to the development of new treatments for this devastating disease.”
The Medical Research Council invested £1.74 million in the programme of research, alongside major funding from the Wellcome Trust, the Welsh Assembly Government and the Alzheimer’s Research Trust, among others.
2
Data from the GWAS research was shared with a further French-led study, which has revealed compelling evidence for a third gene associated with Alzheimer’s called CR1.
Notes:
1. The Medical Research Council is dedicated to improving human health through excellent science. It invests on behalf of the UK taxpayer. Its work ranges from molecular level science to public health research, carried out in universities, hospitals and a network of its own units and institutes. The results have led to some of the most significant discoveries in medical science and benefited the health and wealth of millions of people in the UK and around the world. www.mrc.ac.uk
2. The Genome-Wide Association Study (GWAS) identifies variants at CLU and PICALM associated with Alzheimer’s disease’ by Williams et al is published in Nature Genetics.
3. Both CLU and PICALM highlight new pathways that lead to Alzheimer's disease. The CLU gene produces clusterin which normally acts to protect the brain in a variety of ways. Variation in this gene could remove this protection and contribute to Alzheimer's development. PICALM is important at synapses - connections between brain cells - and is involved in the transport of molecules into and inside of nerve cells, helping form memories and other brain functions. We know that the health of synapses is closely related to memory performance in Alzheimer's disease, thus changes in genes which affect synapses are likely to have a direct effect on disease development.
4. Professor Julie Williams is Professor of Neuropsychology Genetics at the Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics based at the University of Cardiff. For more information about the new flagship centre in Cardiff visit:
http://www.mrc.ac.uk/Newspublications/News/MRC006193
5. Alzheimer's disease is the most common cause of dementia, affecting around 417,000 people in the UK. Alzheimer's disease, first described by the German neurologist Alois Alzheimer, is a physical disease affecting the brain. During the course of the disease, 'plaques' and 'tangles' develop in the structure of the brain, leading to the death of brain cells. People with Alzheimer's also have a shortage of some important chemicals in their brains. These chemicals are involved with the transmission of messages within the brain
6. Following the establishment of a collaborative consortium between Europe and the United States, the investigation involved researchers from universities in Cardiff, London, Cambridge, Nottingham, Southampton, Manchester, Oxford, Bristol and Belfast, as well as Irish, German, Belgian, Greek and American institutions.
Press contact: 020 7637 6011
press.office@headoffice.mrc.ac.uk
http://www.mrc.ac.uk/consumption/groups/public/documents/content/mrc006341.pdf
SEE ALZHEIMER'S AND CJD
http://betaamyloidcjd.blogspot.com/
TSS
Monday, June 29, 2009
Beyond the prion principle
News and Views Nature 459, 924-925 (18 June 2009) doi:10.1038/459924a; Published online 17 June 2009
CELL BIOLOGY
Beyond the prion principle
Adriano Aguzzi
It seems that many misfolded proteins can act like prions — spreading disease by imparting their misshapen structure to normal cellular counterparts. But how common are bona fide prions really?
The protein-only hypothesis of prion propagation is steadily gaining ground. First envisaged by John Stanley Griffith1 and later formalized by Stanley Prusiner2, this theory proposes the existence of an infectious agent composed solely of protein. Three reports, two in Nature Cell Biology3,4 and one in The Journal of Cell Biology5, now contend that, far from being confined to the rare prion diseases, prion-like transmission of altered proteins may occur in several human diseases of the brain and other organs.
Prions are now accepted as causing the transmissible spongiform encephalopathies, which include scrapie in sheep, bovine spongiform encephalopathy (BSE, or mad cow disease) and its human variant Creutzfeldt–Jakob disease. The infectious prion particle is made up of PrPSc, a misfolded and aggregated version of a normal protein known as PrPC. Like the growth of crystals, PrPSc propagates by recruiting monomeric PrPC into its aggregates — a process that has been replicated in vitro6 and in transgenic mice7. The breakage of PrPSc aggregates represents the actual replicative event, as it multiplies the number of active seeds8.
Apart from prion diseases, the misfolding and aggregation of proteins into various harmful forms, which are collectively known as amyloid, causes a range of diseases of the nervous system and other organs. The clinical characteristics of amyloidoses, however, gave little reason to suspect a relationship to prion diseases. Hints of prion-like behaviour in amyloid have emerged from studies of Alzheimer’s disease and Parkinson’s disease. Alzheimer’s disease had been suspected to be transmissible for some time: an early report9 of disease transmission to hamsters through white blood cells from people with Alzheimer’s disease caused great consternation, but was never reproduced. Much more tantalizing evidence came from the discovery10,11 that aggregates of the amyloid-â (Aâ) peptide found in the brain of people with Alzheimer’s disease could be transmitted to the brain of mice engineered to produce large amounts of the Aâ precursor protein APP. Another study12 has shown that healthy tissue grafted into the brain of people with Parkinson’s disease acquires intracellular Lewy bodies — aggregates of the Parkinson’s disease-associated protein á-synuclein. This suggests prion-like transmission of diseased protein from the recipient’s brain to the grafted cells.
These findings10–12 raise a provocative question. If protein aggregation depends on the introduction of ‘seeds’ and on the availability of the monomeric precursor, and if, as has been suggested13, amyloid represents the primordial state of all proteins, wouldn’t all proteins — under appropriate conditions — behave like prions in the presence of sufficient precursor? Acceptance of this concept is gaining momentum. For one thing, an increasing wealth of traits is being found in yeast, fungi and bacteria that can best be explained as prion-like phenomena (see table). And now, Ren and colleagues3 provide evidence for prion-like spread of polyglutamine (polyQ)- containing protein aggregates, which are similar to the aggregates found in Huntington’s disease. They show that polyQ aggregates can be taken up from the outside by mammalian cells. Once in the cytosol, the polyQ aggregates can grow by recruiting endogenous polyQ. Clavaguera et al.4 report similar findings in a mouse model of tauopathy, a neurodegenerative disease caused by intraneuronal aggregation of the microtubule-associated tau protein. Injection of mutant human tau into the brain of mice overexpressing normal human tau transmitted tauopathy, with intracellular aggregation of previously normal tau and spread of aggregates to neighbouring regions of the brain. Notably, full-blown tauopathy was not induced in mice that did not express human tau. Assuming that tau pathology wasn’t elicited by some indirect pathway (some mice overexpressing mutated human tau develop protein tangles even when exposed to un related amyloid aggregates14), this sequence of events is reminiscent of prions. Finally, Frost and colleagues5 show that extracellular tau aggregates can be taken up by cells in culture. Hence, tau can attack and penetrate cells from the outside, sporting predatory behaviour akin to that of prions.
Yet there is one crucial difference between actual prion diseases and diseases caused by other prion-like proteins (let’s call them prionoids) described so far (see table). The behaviour of prions is entirely comparable to that of any other infectious agent: for instance, prions are transmissible between individuals and often across species, and can be assayed with classic microbiological techniques, including titration by bioassay. Accordingly, prion diseases were long thought to be caused by viruses, and BSE created a worldwide panic similar to that currently being provoked by influenza. By contrast, although prionoids can ‘infect’ neighbouring molecules and sometimes even neighbouring cells, they do not spread within communities or cause epidemics such as those seen with BSE.
So, should any amyloid deserve an upgrade to a bone fide prion status? Currently, amyloid A (AA) amyloidosis may be the most promising candidate for a truly infectious disease caused by a self-propagating protein other than PrPSc. AA amyloid consists of orderly aggregated fragments of the SAA protein, and its deposition damages many organs of the body. Seeds of AA amyloid can be excreted in faeces15, and can induce amyloidosis if taken up orally (at least in geese)16. Also, AA amyloid may be transmitted between mice by transfusion of white blood cells17. So, like entero viruses and, perhaps, sheep scrapie prions, AA amyloid seems to display all the elements of a complete infectious life cycle, including uptake, replication and release from its host.
There are intriguing evolutionary implications to the above findings. If prionoids are ubiquitous, why didn’t evolution erect barriers to their pervasiveness? Maybe it is because the molecular transmissibility of aggregated states can sometimes be useful. Indeed, aggregation of the Sup35 protein, which leads to a prion-like phenomenon in yeast, may promote evolutionary adaptation by allowing yeast cells to temporarily activate DNA sequences that are normally untranslated18. Mammals have developed receptors for aggregates, and ironically PrPC may be one of them19, although these receptors have not been reported to mediate protective functions. Therefore, we shouldn’t be shocked if instances of beneficial prionoids emerge in mammals as well. ¦
Adriano Aguzzi is at the Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland. e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000029/!x-usc:mailto:adriano.aguzzi@usz.ch
1. Griffith, J. S. Nature 215, 1043–1044 (1967). 2. Prusiner, S. B. Science 216, 136–144 (1982). 3. Ren, P.-H. et al. Nature Cell Biol. 11, 219–225 (2009). 4. Clavaguera, F. et al. Nature Cell Biol. doi:10.1038/ncb1901 (2009). 5. Frost, B., Jacks, R. L. & Diamond, M. I. J. Biol. Chem. 284, 12845–12852 (2009). 6. Castilla, J., Saá, P., Hetz, C. & Soto, C. Cell 121, 195–206 (2005). 7. Sigurdson, C. J. et al. Proc. Natl Acad. Sci. USA 106, 304–309 (2009). 8. Aguzzi, A. & Polymenidou, M. Cell 116, 313–327 (2004). 9. Manuelidis, E. E. et al. Proc. Natl Acad. Sci. USA 85, 4898–4901 (1988). 10. Kane, M. D. et al. J. Neurosci. 20, 3606–3611 (2000). 11. Meyer-Luehmann, M. et al. Science 313, 1781–1784 (2006). 12. Li, J.-Y. et al. Nature Med. 14, 501–503 (2008). 13. Chiti, F. & Dobson, C. M. Annu. Rev. Biochem. 75, 333–366 (2006). 14. GÖtz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Science 293, 1491–1495 (2001). 15. Zhang, B. et al. Proc. Natl Acad. Sci. USA 105, 7263–7268 (2008). 16. Solomon, A. et al. Proc. Natl Acad. Sci. USA 104, 10998–11001 (2007). 17. Sponarova, J., NystrÖm, S. N. & Westermark, G. T. PLoS ONE 3, e3308 (2008). 18. True, H. L. & Lindquist, S. L. Nature 407, 477–483 (2000). 19. Laurén, J. et al. Nature 457, 1128–1132 (2009). PRIONS AND POTENTIAL PRIONOIDS Disease Protein Molecular transmissibility Infectious life cycle Prion diseases PrPSc Yes Yes Alzheimer’s disease Amyloid-ß Yes Not shown Tauopathies Tau Yes Not shown Parkinson’s disease a-Synuclein Host-to-graft Not shown AA amyloidosis Amyloid A Yes Possible Huntington’s disease Polyglutamine Yes Not shown Phenotype Protein Molecular transmissibility Infectious life cycle Suppressed translational termination (yeast) Sup35 Yes Not shown Heterokaryon incompatibility (filamentous fungi) Het-s Yes Not shown Biofilm promotion (bacteria) CsgA Yes Not shown In humans and animals, infectious prion diseases are caused by PrPSc, which spreads by recruiting its monomeric precursor PrPC into aggregates. Aggregates then multiply by breakage, a process that is termed molecular transmissibility. Other proteins involved in disease and in phenotypes of fungi and bacteria, can also undergo self-sustaining aggregation, but none of these ‘prionoid’ proteins behaves like typical infectious agents, nor do any of them enact a complete infectious life cycle — with the possible exception of AA amyloid. Correction In the News & Views article “Immunology: Immunity’s ancient arms” by Gary W. Litman and John P. Cannon (Nature 459, 784–786; 2009), the name of the fi rst author of the Nature paper under discussion was misspelt. The author’s name is P. Guo, not Gou as published.
© 2009 Macmillan Publishers Limited. All rights reserved
http://www.nature.com/nature/journal/v459/n7249/full/459924a.html
Thursday, February 26, 2009
'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
93/01.05/4.1tss
http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
snip...
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...
snip...
http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf
And NONE of this is relevant to BSE?
There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.
http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf
THE LINE TO TAKE.
http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992
CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
also, see the increase of Alzheimer's from 1981 to 1986
http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
see full text ;
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
Elsevier Editorial System(tm) for The Lancet Infectious Diseases Manuscript Draft Manuscript Number:
Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory
Article Type: Personal View Corresponding
snip...see full text 31 pages ;
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=090000648027c28e&disposition=attachment&contentType=pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
Sunday, June 7, 2009
ALZHEIMER'S DISEASE IS TRANSMISSIBLE
http://betaamyloidcjd.blogspot.com/2009/06/alzheimers-disease-is-transmissible.html
Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734.
Full Text
Tue, 13 Feb 2001 JAMA Vol. 285 No. 6, February 14, 2001 Letters
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor:
In their Research Letter in JAMA. 2000;284:2322-2323, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
To the Editor:
At the time of my mother's death, various diagnoses were advanced such as "rapid progressive Alzheimer disease," psychosis, and dementia. Had I not persisted and personally sought and arranged a brain autopsy, her death certificate would have read cardiac failure and not CJD.
Through CJD Voice1 I have corresponded with hundreds of grief-stricken families who are so devastated by this horrific disease that brain autopsy is the furthest thing from their minds. In my experience, very few physicians suggest it to the family. After the death and when families reflect that they never were sure what killed their loved one it is too late to find the true cause of death. In the years since my mother died I think that the increasing awareness of the nature of CJD has only resulted in fewer pathologists being willing to perform an autopsy in a suspected case of CJD.
People with CJD may die with incorrect diagnoses of dementia, psychosis, Alzheimer disease, and myriad other neurological diseases. The true cause of death will only be known if brain autopsies are suggested to the families. Too often the physician's comment is, "Well, it could be CJD but that is so rare it isn't likely."
Until CJD is required to be reported to state health departments, as other diseases are, there will be no accurate count of CJD deaths in the United States and thus no way to know if the number of deaths is decreasing, stable, or increasing as it has recently in the United Kingdom.
Dorothy E. Kraemer Stillwater, Okla
In Reply:
Mr Singeltary and Ms Kraemer express an underlying concern that our recently reported mortality surveillance estimate of about 1 CJD case per million population per year in the United States since 1985 may greatly underestimate the true incidence of this disease. Based on evidence from epidemiologic investigations both within and outside the United States, we believe that these national estimates are reasonably accurate.
Even during the 1990s in the United Kingdom, where much attention and public health resources have been devoted to prion disease surveillance, the reported incidence of classic CJD is similar to that reported in the United States.
In addition, in 1996, active US surveillance for CJD and new variant (nv) CJD in 5 sites detected no evidence of the occurrence of nvCJD and showed that 86% of the CJD cases in these sites were identifiable through routinely collected mortality data.
Our report provides additional evidence against the occurrence of nvCJD in the United States based on national mortality data analyses and enhanced surveillance. It specifically mentions a new center for improved pathology surveillance. We hope that the described enhancements along with the observations of Singeltary and Kraemer will encourage medical care providers to suggest brain autopsies for more suspected CJD cases to facilitate the identification of potentially misdiagnosed CJD cases and to help monitor the possible occurrence of nvCJD.
Creutzfeldt-Jakob disease is not on the list of nationally notifiable diseases. In those states where surveillance personnel indicate that making this disease officially notifiable would meaningfully facilitate collection of data that are needed to monitor the incidence of CJD and nvCJD, including the obtaining of brain autopsy results, we encourage such a change. However, adding CJD to the notifiable diseases surveillance system may lead to potentially wasteful, duplicative reporting because the vast majority of the diagnosed cases would also be reported through the mortality surveillance system.
Furthermore, making CJD a notifiable disease may not necessarily help identify undiagnosed CJD cases. The unique characteristics of CJD make mortality data a useful surrogate for ongoing surveillance. Unlike many other neurologic diseases, CJD is invariably fatal and in most cases rapidly progressive and distinguishable clinically from other neurologic diseases.
Because CJD is least accurately diagnosed early in the course of the illness, notifiable disease surveillance of CJD could be less accurate than mortality surveillance of CJD. In addition, because death as a condition is more completely and consistently reported, mortality surveillance has the advantage of being ongoing and readily available.
The absence of CJD and nvCJD from the list of nationally notifiable diseases should not be interpreted to mean that they are not important to public health; this list does not include all such diseases. We encourage medical caregivers to report to or consult with appropriate public health authorities about any diagnosed case of a transmissible disease for which a special public health response may be needed, including nvCJD, and any patient in whom iatrogenic transmission of CJD may be suspected.
Robert V. Gibbons, MD, MPH Robert C. Holman, MS Ermias D. Belay, MD Lawrence B. Schonberger, MD, MPH Division of Viral and Rickettsial Diseases National Center for Infectious Diseases Centers for Disease Control and Prevention Atlanta, Ga
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama
Full Text Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734.
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama
Book
The Pathological Protein
Publisher Springer New York DOI 10.1007/b97488 Copyright 2003 ISBN 978-0-387-95508-7 (Print) 978-0-387-21755-0 (Online) DOI 10.1007/0-387-21755-X_14 Pages 223-237 Subject Collection Humanities, Social Sciences and Law SpringerLink
Laying Odds
snip...
Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.
snip...
http://www.springerlink.com/content/r2k2622661473336/
http://books.google.com/books?id=ePbrQNFrHtoC&pg=PA223&lpg=PA223&dq=SINGELTARY+pathological+protein+it
The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.
http://www.cjdfoundation.org/fact.html
http://cjdusa.blogspot.com/
SPORADIC CJD CASES RISING IN U.S.A 2009 UPDATE
Monday, April 20, 2009
National Prion Disease Pathology Surveillance Center Cases Examined1 (December 31, 2008)
April 20, 2009
National Prion Disease Pathology Surveillance Center Cases Examined1 (December 31, 2008)
National Prion Disease Pathology Surveillance Center Cases Examined1
(December 31, 2008)
Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD
1996 & earlier 42 32 28 4 0 0
1997 115 68 59 9 0 0
1998 93 53 45 7 1 0
1999 115 69 61 8 0 0
2000 151 103 89 14 0 0
2001 210 118 108 9 0 0
2002 258 147 123 22 2 0
2003 273 176 135 41 0 0
2004 335 184 162 21 0 13
2005 346 193 154 38 1 0
2006 380 192 159 32 0 14
2007 370 212 185 26 0 0
2008 383 228 182 23 0 0
TOTAL 30715 17756 1490 254 4 2
1 Listed based on the year of death or, if not available, on year of referral; 2 Cases with suspected prion disease for which brain tissue and/or blood (in familial cases) were submitted; 3 Disease acquired in the United Kingdom; 4 Disease acquired in Saudi Arabia; 5 Includes 20 cases in which the diagnosis is pending, and 17 inconclusive cases; 6 Includes 25 cases with type determination pending in which the diagnosis of vCJD has been excluded.
Rev 2/13/09 National
http://www.cjdsurveillance.com/pdf/case-table.pdf
http://www.cjdsurveillance.com/resources-casereport.html
http://www.aan.com/news/?event=read&article_id=4397&page=72.45.45
*5 Includes 20 cases in which the diagnosis is pending, and 17 inconclusive cases; *6 Includes 25 cases with type determination pending in which the diagnosis of vCJD has been excluded.
Greetings,
it would be interesting to know what year these atypical cases occurred, as opposed to lumping them in with the totals only.
are they accumulating ?
did they occur in one year, two years, same state, same city ?
location would be very interesting ?
age group ?
sex ?
how was it determined that nvCJD was ruled out ?
from 1997, the year i started dealing with this nightmare, there were 28 cases (per this report), up until 2007 where the total was 185 cases (per this report), and to date 2008 is at 182. a staggering increase in my opinion, for something that just happens spontaneously as some would have us believe. i don't believe it, not in 85%+ of all sporadic CJD cases. actually, i do not believe yet that anyone has proven that any of the sporadic CJD cases have been proven to be a spontaneous misfolding of a protein. there are many potential routes and sources for the sporadic CJD's. ...TSS
please see full text here ;
http://prionunitusaupdate2008.blogspot.com/2009/04/national-prion-disease-pathology.html
Rare BSE mutation raises concerns over risks to public health
SIR - Atypical forms (known as H- and L-type) of bovine spongiform encephalopathy (BSE) have recently appeared in several European countries as well as in Japan, Canada and the United States. This raises the unwelcome possibility that variant Creutzfeldt-Jakob disease (vCJD) could increase in the human population. Of the atypical BSE cases tested so far, a mutation in the prion protein gene (PRNP) has been detected in just one, a cow in Alabama with BSE; her healthy calf also carried the mutation (J. A. Richt and S. M. Hall PLoS Pathog. 4, e1000156; 2008). This raises the possibility that the disease could occasionally be genetic in origin. Indeed, the report of the UK BSE Inquiry in 2000 suggested that the UK epidemic had most likely originated from such a mutation and argued against the scrapierelated assumption. Such rare potential pathogenic PRNP mutations could occur in countries at present considered to be free of BSE, such as Australia and New Zealand. So it is important to maintain strict surveillance for BSE in cattle, with rigorous enforcement of the ruminant feed ban (many countries still feed ruminant proteins to pigs). Removal of specified risk material, such as brain and spinal cord, from cattle at slaughter prevents infected material from entering the human food chain. Routine genetic screening of cattle for PRNP mutations, which is now available, could provide additional data on the risk to the public. Because the point mutation identified in the Alabama animals is identical to that responsible for the commonest type of familial (genetic) CJD in humans, it is possible that the resulting infective prion protein might cross the bovine-human species barrier more easily. Patients with vCJD continue to be identified. The fact that this is happening less often should not lead to relaxation of the controls necessary to prevent future outbreaks. Malcolm A. Ferguson-Smith Cambridge University Department of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000029/!x-usc:mailto:maf12@cam.ac.uk Jürgen A. Richt College of Veterinary Medicine, Kansas State University, K224B Mosier Hall, Manhattan, Kansas 66506-5601, USA
NATUREVol 45726 February 2009
http://www.nature.com/nature/journal/v457/n7233/full/4571079b.html
see full text ;
Monday, May 11, 2009
Rare BSE mutation raises concerns over risks to public health
http://bse-atypical.blogspot.com/2009/05/rare-bse-mutation-raises-concerns-over.html
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
http://betaamyloidcjd.blogspot.com/
TSS
CELL BIOLOGY
Beyond the prion principle
Adriano Aguzzi
It seems that many misfolded proteins can act like prions — spreading disease by imparting their misshapen structure to normal cellular counterparts. But how common are bona fide prions really?
The protein-only hypothesis of prion propagation is steadily gaining ground. First envisaged by John Stanley Griffith1 and later formalized by Stanley Prusiner2, this theory proposes the existence of an infectious agent composed solely of protein. Three reports, two in Nature Cell Biology3,4 and one in The Journal of Cell Biology5, now contend that, far from being confined to the rare prion diseases, prion-like transmission of altered proteins may occur in several human diseases of the brain and other organs.
Prions are now accepted as causing the transmissible spongiform encephalopathies, which include scrapie in sheep, bovine spongiform encephalopathy (BSE, or mad cow disease) and its human variant Creutzfeldt–Jakob disease. The infectious prion particle is made up of PrPSc, a misfolded and aggregated version of a normal protein known as PrPC. Like the growth of crystals, PrPSc propagates by recruiting monomeric PrPC into its aggregates — a process that has been replicated in vitro6 and in transgenic mice7. The breakage of PrPSc aggregates represents the actual replicative event, as it multiplies the number of active seeds8.
Apart from prion diseases, the misfolding and aggregation of proteins into various harmful forms, which are collectively known as amyloid, causes a range of diseases of the nervous system and other organs. The clinical characteristics of amyloidoses, however, gave little reason to suspect a relationship to prion diseases. Hints of prion-like behaviour in amyloid have emerged from studies of Alzheimer’s disease and Parkinson’s disease. Alzheimer’s disease had been suspected to be transmissible for some time: an early report9 of disease transmission to hamsters through white blood cells from people with Alzheimer’s disease caused great consternation, but was never reproduced. Much more tantalizing evidence came from the discovery10,11 that aggregates of the amyloid-â (Aâ) peptide found in the brain of people with Alzheimer’s disease could be transmitted to the brain of mice engineered to produce large amounts of the Aâ precursor protein APP. Another study12 has shown that healthy tissue grafted into the brain of people with Parkinson’s disease acquires intracellular Lewy bodies — aggregates of the Parkinson’s disease-associated protein á-synuclein. This suggests prion-like transmission of diseased protein from the recipient’s brain to the grafted cells.
These findings10–12 raise a provocative question. If protein aggregation depends on the introduction of ‘seeds’ and on the availability of the monomeric precursor, and if, as has been suggested13, amyloid represents the primordial state of all proteins, wouldn’t all proteins — under appropriate conditions — behave like prions in the presence of sufficient precursor? Acceptance of this concept is gaining momentum. For one thing, an increasing wealth of traits is being found in yeast, fungi and bacteria that can best be explained as prion-like phenomena (see table). And now, Ren and colleagues3 provide evidence for prion-like spread of polyglutamine (polyQ)- containing protein aggregates, which are similar to the aggregates found in Huntington’s disease. They show that polyQ aggregates can be taken up from the outside by mammalian cells. Once in the cytosol, the polyQ aggregates can grow by recruiting endogenous polyQ. Clavaguera et al.4 report similar findings in a mouse model of tauopathy, a neurodegenerative disease caused by intraneuronal aggregation of the microtubule-associated tau protein. Injection of mutant human tau into the brain of mice overexpressing normal human tau transmitted tauopathy, with intracellular aggregation of previously normal tau and spread of aggregates to neighbouring regions of the brain. Notably, full-blown tauopathy was not induced in mice that did not express human tau. Assuming that tau pathology wasn’t elicited by some indirect pathway (some mice overexpressing mutated human tau develop protein tangles even when exposed to un related amyloid aggregates14), this sequence of events is reminiscent of prions. Finally, Frost and colleagues5 show that extracellular tau aggregates can be taken up by cells in culture. Hence, tau can attack and penetrate cells from the outside, sporting predatory behaviour akin to that of prions.
Yet there is one crucial difference between actual prion diseases and diseases caused by other prion-like proteins (let’s call them prionoids) described so far (see table). The behaviour of prions is entirely comparable to that of any other infectious agent: for instance, prions are transmissible between individuals and often across species, and can be assayed with classic microbiological techniques, including titration by bioassay. Accordingly, prion diseases were long thought to be caused by viruses, and BSE created a worldwide panic similar to that currently being provoked by influenza. By contrast, although prionoids can ‘infect’ neighbouring molecules and sometimes even neighbouring cells, they do not spread within communities or cause epidemics such as those seen with BSE.
So, should any amyloid deserve an upgrade to a bone fide prion status? Currently, amyloid A (AA) amyloidosis may be the most promising candidate for a truly infectious disease caused by a self-propagating protein other than PrPSc. AA amyloid consists of orderly aggregated fragments of the SAA protein, and its deposition damages many organs of the body. Seeds of AA amyloid can be excreted in faeces15, and can induce amyloidosis if taken up orally (at least in geese)16. Also, AA amyloid may be transmitted between mice by transfusion of white blood cells17. So, like entero viruses and, perhaps, sheep scrapie prions, AA amyloid seems to display all the elements of a complete infectious life cycle, including uptake, replication and release from its host.
There are intriguing evolutionary implications to the above findings. If prionoids are ubiquitous, why didn’t evolution erect barriers to their pervasiveness? Maybe it is because the molecular transmissibility of aggregated states can sometimes be useful. Indeed, aggregation of the Sup35 protein, which leads to a prion-like phenomenon in yeast, may promote evolutionary adaptation by allowing yeast cells to temporarily activate DNA sequences that are normally untranslated18. Mammals have developed receptors for aggregates, and ironically PrPC may be one of them19, although these receptors have not been reported to mediate protective functions. Therefore, we shouldn’t be shocked if instances of beneficial prionoids emerge in mammals as well. ¦
Adriano Aguzzi is at the Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland. e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000029/!x-usc:mailto:adriano.aguzzi@usz.ch
1. Griffith, J. S. Nature 215, 1043–1044 (1967). 2. Prusiner, S. B. Science 216, 136–144 (1982). 3. Ren, P.-H. et al. Nature Cell Biol. 11, 219–225 (2009). 4. Clavaguera, F. et al. Nature Cell Biol. doi:10.1038/ncb1901 (2009). 5. Frost, B., Jacks, R. L. & Diamond, M. I. J. Biol. Chem. 284, 12845–12852 (2009). 6. Castilla, J., Saá, P., Hetz, C. & Soto, C. Cell 121, 195–206 (2005). 7. Sigurdson, C. J. et al. Proc. Natl Acad. Sci. USA 106, 304–309 (2009). 8. Aguzzi, A. & Polymenidou, M. Cell 116, 313–327 (2004). 9. Manuelidis, E. E. et al. Proc. Natl Acad. Sci. USA 85, 4898–4901 (1988). 10. Kane, M. D. et al. J. Neurosci. 20, 3606–3611 (2000). 11. Meyer-Luehmann, M. et al. Science 313, 1781–1784 (2006). 12. Li, J.-Y. et al. Nature Med. 14, 501–503 (2008). 13. Chiti, F. & Dobson, C. M. Annu. Rev. Biochem. 75, 333–366 (2006). 14. GÖtz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Science 293, 1491–1495 (2001). 15. Zhang, B. et al. Proc. Natl Acad. Sci. USA 105, 7263–7268 (2008). 16. Solomon, A. et al. Proc. Natl Acad. Sci. USA 104, 10998–11001 (2007). 17. Sponarova, J., NystrÖm, S. N. & Westermark, G. T. PLoS ONE 3, e3308 (2008). 18. True, H. L. & Lindquist, S. L. Nature 407, 477–483 (2000). 19. Laurén, J. et al. Nature 457, 1128–1132 (2009). PRIONS AND POTENTIAL PRIONOIDS Disease Protein Molecular transmissibility Infectious life cycle Prion diseases PrPSc Yes Yes Alzheimer’s disease Amyloid-ß Yes Not shown Tauopathies Tau Yes Not shown Parkinson’s disease a-Synuclein Host-to-graft Not shown AA amyloidosis Amyloid A Yes Possible Huntington’s disease Polyglutamine Yes Not shown Phenotype Protein Molecular transmissibility Infectious life cycle Suppressed translational termination (yeast) Sup35 Yes Not shown Heterokaryon incompatibility (filamentous fungi) Het-s Yes Not shown Biofilm promotion (bacteria) CsgA Yes Not shown In humans and animals, infectious prion diseases are caused by PrPSc, which spreads by recruiting its monomeric precursor PrPC into aggregates. Aggregates then multiply by breakage, a process that is termed molecular transmissibility. Other proteins involved in disease and in phenotypes of fungi and bacteria, can also undergo self-sustaining aggregation, but none of these ‘prionoid’ proteins behaves like typical infectious agents, nor do any of them enact a complete infectious life cycle — with the possible exception of AA amyloid. Correction In the News & Views article “Immunology: Immunity’s ancient arms” by Gary W. Litman and John P. Cannon (Nature 459, 784–786; 2009), the name of the fi rst author of the Nature paper under discussion was misspelt. The author’s name is P. Guo, not Gou as published.
© 2009 Macmillan Publishers Limited. All rights reserved
http://www.nature.com/nature/journal/v459/n7249/full/459924a.html
Thursday, February 26, 2009
'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
93/01.05/4.1tss
http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
snip...
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...
snip...
http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf
And NONE of this is relevant to BSE?
There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.
http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf
THE LINE TO TAKE.
http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992
CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
also, see the increase of Alzheimer's from 1981 to 1986
http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
see full text ;
http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
Elsevier Editorial System(tm) for The Lancet Infectious Diseases Manuscript Draft Manuscript Number:
Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory
Article Type: Personal View Corresponding
snip...see full text 31 pages ;
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=090000648027c28e&disposition=attachment&contentType=pdf
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
Sunday, June 7, 2009
ALZHEIMER'S DISEASE IS TRANSMISSIBLE
http://betaamyloidcjd.blogspot.com/2009/06/alzheimers-disease-is-transmissible.html
Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734.
Full Text
Tue, 13 Feb 2001 JAMA Vol. 285 No. 6, February 14, 2001 Letters
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor:
In their Research Letter in JAMA. 2000;284:2322-2323, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
To the Editor:
At the time of my mother's death, various diagnoses were advanced such as "rapid progressive Alzheimer disease," psychosis, and dementia. Had I not persisted and personally sought and arranged a brain autopsy, her death certificate would have read cardiac failure and not CJD.
Through CJD Voice1 I have corresponded with hundreds of grief-stricken families who are so devastated by this horrific disease that brain autopsy is the furthest thing from their minds. In my experience, very few physicians suggest it to the family. After the death and when families reflect that they never were sure what killed their loved one it is too late to find the true cause of death. In the years since my mother died I think that the increasing awareness of the nature of CJD has only resulted in fewer pathologists being willing to perform an autopsy in a suspected case of CJD.
People with CJD may die with incorrect diagnoses of dementia, psychosis, Alzheimer disease, and myriad other neurological diseases. The true cause of death will only be known if brain autopsies are suggested to the families. Too often the physician's comment is, "Well, it could be CJD but that is so rare it isn't likely."
Until CJD is required to be reported to state health departments, as other diseases are, there will be no accurate count of CJD deaths in the United States and thus no way to know if the number of deaths is decreasing, stable, or increasing as it has recently in the United Kingdom.
Dorothy E. Kraemer Stillwater, Okla
In Reply:
Mr Singeltary and Ms Kraemer express an underlying concern that our recently reported mortality surveillance estimate of about 1 CJD case per million population per year in the United States since 1985 may greatly underestimate the true incidence of this disease. Based on evidence from epidemiologic investigations both within and outside the United States, we believe that these national estimates are reasonably accurate.
Even during the 1990s in the United Kingdom, where much attention and public health resources have been devoted to prion disease surveillance, the reported incidence of classic CJD is similar to that reported in the United States.
In addition, in 1996, active US surveillance for CJD and new variant (nv) CJD in 5 sites detected no evidence of the occurrence of nvCJD and showed that 86% of the CJD cases in these sites were identifiable through routinely collected mortality data.
Our report provides additional evidence against the occurrence of nvCJD in the United States based on national mortality data analyses and enhanced surveillance. It specifically mentions a new center for improved pathology surveillance. We hope that the described enhancements along with the observations of Singeltary and Kraemer will encourage medical care providers to suggest brain autopsies for more suspected CJD cases to facilitate the identification of potentially misdiagnosed CJD cases and to help monitor the possible occurrence of nvCJD.
Creutzfeldt-Jakob disease is not on the list of nationally notifiable diseases. In those states where surveillance personnel indicate that making this disease officially notifiable would meaningfully facilitate collection of data that are needed to monitor the incidence of CJD and nvCJD, including the obtaining of brain autopsy results, we encourage such a change. However, adding CJD to the notifiable diseases surveillance system may lead to potentially wasteful, duplicative reporting because the vast majority of the diagnosed cases would also be reported through the mortality surveillance system.
Furthermore, making CJD a notifiable disease may not necessarily help identify undiagnosed CJD cases. The unique characteristics of CJD make mortality data a useful surrogate for ongoing surveillance. Unlike many other neurologic diseases, CJD is invariably fatal and in most cases rapidly progressive and distinguishable clinically from other neurologic diseases.
Because CJD is least accurately diagnosed early in the course of the illness, notifiable disease surveillance of CJD could be less accurate than mortality surveillance of CJD. In addition, because death as a condition is more completely and consistently reported, mortality surveillance has the advantage of being ongoing and readily available.
The absence of CJD and nvCJD from the list of nationally notifiable diseases should not be interpreted to mean that they are not important to public health; this list does not include all such diseases. We encourage medical caregivers to report to or consult with appropriate public health authorities about any diagnosed case of a transmissible disease for which a special public health response may be needed, including nvCJD, and any patient in whom iatrogenic transmission of CJD may be suspected.
Robert V. Gibbons, MD, MPH Robert C. Holman, MS Ermias D. Belay, MD Lawrence B. Schonberger, MD, MPH Division of Viral and Rickettsial Diseases National Center for Infectious Diseases Centers for Disease Control and Prevention Atlanta, Ga
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama
Full Text Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734.
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama
Book
The Pathological Protein
Publisher Springer New York DOI 10.1007/b97488 Copyright 2003 ISBN 978-0-387-95508-7 (Print) 978-0-387-21755-0 (Online) DOI 10.1007/0-387-21755-X_14 Pages 223-237 Subject Collection Humanities, Social Sciences and Law SpringerLink
Laying Odds
snip...
Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.
snip...
http://www.springerlink.com/content/r2k2622661473336/
http://books.google.com/books?id=ePbrQNFrHtoC&pg=PA223&lpg=PA223&dq=SINGELTARY+pathological+protein+it
The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.
http://www.cjdfoundation.org/fact.html
http://cjdusa.blogspot.com/
SPORADIC CJD CASES RISING IN U.S.A 2009 UPDATE
Monday, April 20, 2009
National Prion Disease Pathology Surveillance Center Cases Examined1 (December 31, 2008)
April 20, 2009
National Prion Disease Pathology Surveillance Center Cases Examined1 (December 31, 2008)
National Prion Disease Pathology Surveillance Center Cases Examined1
(December 31, 2008)
Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD
1996 & earlier 42 32 28 4 0 0
1997 115 68 59 9 0 0
1998 93 53 45 7 1 0
1999 115 69 61 8 0 0
2000 151 103 89 14 0 0
2001 210 118 108 9 0 0
2002 258 147 123 22 2 0
2003 273 176 135 41 0 0
2004 335 184 162 21 0 13
2005 346 193 154 38 1 0
2006 380 192 159 32 0 14
2007 370 212 185 26 0 0
2008 383 228 182 23 0 0
TOTAL 30715 17756 1490 254 4 2
1 Listed based on the year of death or, if not available, on year of referral; 2 Cases with suspected prion disease for which brain tissue and/or blood (in familial cases) were submitted; 3 Disease acquired in the United Kingdom; 4 Disease acquired in Saudi Arabia; 5 Includes 20 cases in which the diagnosis is pending, and 17 inconclusive cases; 6 Includes 25 cases with type determination pending in which the diagnosis of vCJD has been excluded.
Rev 2/13/09 National
http://www.cjdsurveillance.com/pdf/case-table.pdf
http://www.cjdsurveillance.com/resources-casereport.html
http://www.aan.com/news/?event=read&article_id=4397&page=72.45.45
*5 Includes 20 cases in which the diagnosis is pending, and 17 inconclusive cases; *6 Includes 25 cases with type determination pending in which the diagnosis of vCJD has been excluded.
Greetings,
it would be interesting to know what year these atypical cases occurred, as opposed to lumping them in with the totals only.
are they accumulating ?
did they occur in one year, two years, same state, same city ?
location would be very interesting ?
age group ?
sex ?
how was it determined that nvCJD was ruled out ?
from 1997, the year i started dealing with this nightmare, there were 28 cases (per this report), up until 2007 where the total was 185 cases (per this report), and to date 2008 is at 182. a staggering increase in my opinion, for something that just happens spontaneously as some would have us believe. i don't believe it, not in 85%+ of all sporadic CJD cases. actually, i do not believe yet that anyone has proven that any of the sporadic CJD cases have been proven to be a spontaneous misfolding of a protein. there are many potential routes and sources for the sporadic CJD's. ...TSS
please see full text here ;
http://prionunitusaupdate2008.blogspot.com/2009/04/national-prion-disease-pathology.html
Rare BSE mutation raises concerns over risks to public health
SIR - Atypical forms (known as H- and L-type) of bovine spongiform encephalopathy (BSE) have recently appeared in several European countries as well as in Japan, Canada and the United States. This raises the unwelcome possibility that variant Creutzfeldt-Jakob disease (vCJD) could increase in the human population. Of the atypical BSE cases tested so far, a mutation in the prion protein gene (PRNP) has been detected in just one, a cow in Alabama with BSE; her healthy calf also carried the mutation (J. A. Richt and S. M. Hall PLoS Pathog. 4, e1000156; 2008). This raises the possibility that the disease could occasionally be genetic in origin. Indeed, the report of the UK BSE Inquiry in 2000 suggested that the UK epidemic had most likely originated from such a mutation and argued against the scrapierelated assumption. Such rare potential pathogenic PRNP mutations could occur in countries at present considered to be free of BSE, such as Australia and New Zealand. So it is important to maintain strict surveillance for BSE in cattle, with rigorous enforcement of the ruminant feed ban (many countries still feed ruminant proteins to pigs). Removal of specified risk material, such as brain and spinal cord, from cattle at slaughter prevents infected material from entering the human food chain. Routine genetic screening of cattle for PRNP mutations, which is now available, could provide additional data on the risk to the public. Because the point mutation identified in the Alabama animals is identical to that responsible for the commonest type of familial (genetic) CJD in humans, it is possible that the resulting infective prion protein might cross the bovine-human species barrier more easily. Patients with vCJD continue to be identified. The fact that this is happening less often should not lead to relaxation of the controls necessary to prevent future outbreaks. Malcolm A. Ferguson-Smith Cambridge University Department of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000029/!x-usc:mailto:maf12@cam.ac.uk Jürgen A. Richt College of Veterinary Medicine, Kansas State University, K224B Mosier Hall, Manhattan, Kansas 66506-5601, USA
NATUREVol 45726 February 2009
http://www.nature.com/nature/journal/v457/n7233/full/4571079b.html
see full text ;
Monday, May 11, 2009
Rare BSE mutation raises concerns over risks to public health
http://bse-atypical.blogspot.com/2009/05/rare-bse-mutation-raises-concerns-over.html
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
http://betaamyloidcjd.blogspot.com/
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