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.
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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?
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. 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
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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
Showing posts with label USA. Show all posts
Showing posts with label USA. Show all posts
Monday, January 4, 2010
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
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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
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007
FC4.3
Transmission of AA-amyloidosis: Similarities with Prion Disorders
Westermark, P Rudbeck laboratory, Department of Genetics and Pathology, Sweden
The systemic amyloidoses are characterized by widely spread amyloid deposits that can affect virtually every organ in the body. The precursor protein, which varies between different forms is produced at one or several locations, circulates with the plasma and is finally deposited as fibrils in the target organs by mechanisms yet to be determined. In one of the more common forms, systemic AA-amyloidosis, the substrate protein serum AA (SAA) is an acute phase reactant, with significant production only when certain proinflammatory signal substances are upregulated. A persistently high plasma concentration of SAA is a prerequisite for AA-amyloidosis to develop. AA-amyloidosis can easily be induced in many strains of mice by an inflammatory challenge, typically after a long lag phase. This phase is dramatically shortened by administration of amyloid fibrils extracted from an amyloidotic mouse, given intravenously, intra-nasally or given in the drinking water. The fibrillar extract is very potent, active down to pg of protein and facilitates amyloid formation even when given several months before an inflammation is induced. Also amyloid-like fibrils, produced in vitro from synthetic peptides have a clear effect, supporting the idea that the active principle is the misfolded and aggregated protein. AA-amyloidosis occurs in many avian and mammalian species. AA-fibrils from some, but not all species seed murine amyloidosis, showing a species barrier. AA-amyloidosis occurs in species, used as human food and may therefore be a risk factor. Consequently, AA-amyloidosis has similarity with prionoses, differing by the need of an upregulated production of the substrate SAA.
P03.139
Cellular Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein
Hooper, NM1; Parkin, ET1; Watt, NT1; Baybutt, H2; Manson, J2; Hussain, I3; Turner, AJ1 1University of Leeds, Institute of Molecular and Cellular Biology, UK; 2Roslin Institute, Neuropathogenesis Unit, UK; 3GlaxoSmithKline, Neurodegeneration Research, UK
Background: The normal cellular function of the prion protein (PrP), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD) in humans, remains enigmatic. Several studies have reported combinations of Alzheimer’s Disease (AD) and CJD neuropathology and the Val/Met129 polymorphism in the PrP gene has been identified as a risk factor for early-onset AD, leading to speculation that there may be some pathogenic connection between these two neurodegenerative conditions. The amyloid ß (Aß) peptides that cause AD are derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by the ß-secretase (BACE1) and the g-secretase complex. Aim: As both APP and PrP are cleaved by zinc metalloproteases of the ADAM family, we investigated whether PrP alters the proteolytic processing of APP. Results: Here we show that expression of PrP in SH-SY5Y cells dramatically downregulated the cleavage of APP by BACE1 and reduced the secretion of Aß peptides into the conditioned medium by >92%. Conversely, siRNA reduction of endogenous PrP in N2a cells led to an increase in secreted Aß. Furthermore, levels of Aß were significantly increased in the brains of PrP null mice as compared with wild type mice. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases, did not inhibit the BACE1 cleavage of APP. To investigate whether the Val/Met129 polymorphism in human PrPC would alter the production of Aß, brains from mice with the human PrP gene with MM or VV 129 genotypes were analysed. In the MM mice there was a significant increase in Aß in the brains as compared with the VV mice. In the brains of two strains (79A and 87V) of scrapie-infected mice there was a significant increase in Aß peptides as compared to uninfected mice. Conclusions: Together these data reveal a novel function for PrP in regulating the processing of APP through inhibition of BACE1. The increase in APP processing in cells expressing disease-associated forms of PrP and in scrapie-infected brains raises the possibility that the increase in Aß may contribute to the neurodegeneration observed in prion diseases. Funded by the Medical Research Council of Great Britain.
P03.140
Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein through Interaction with Glycosaminoglycans
Griffiths, HH; Parkin, ET; Watt, NT; Turner, AJ; Hooper, NM University of Leeds, Institute of Molecular and Cellular Biology, UK
Background: Proteolytic processing of the amyloid precursor protein (APP) by ßsecretase, BACE1, is the initial step in the production of the amyloid ß (Aß) peptide which is involved in the pathogenesis of Alzheimer’s disease. We have shown that the cellular prion protein (PrP) inhibits the cleavage of APP by BACE1 in cell and animal models. Aim: To investigate the mechanism by which PrP inhibits the action of BACE1. Results: Neither PrPdeltaGPI, which is not membrane attached, nor PrP-CTM, which is anchored by a transmembrane domain and is excluded from cholesterol-rich lipid rafts, reduced cleavage of APP, suggesting that to inhibit the BACE1 cleavage of APP PrP has to be localised to lipid rafts. Coimmunoprecipitation experiments demonstrated that PrP physically interacts with BACE1. However, PrP did not alter the activity of BACE1 towards a fluorogenic peptide substrate nor perturb the dimerisation of BACE1. Using constructs of PrP lacking either the octapeptide repeats or the 4 residues KKRP at the N-terminus of the mature protein (PrPdeltaN), we demonstrate that the KKRP sequence but not the octapeptide repeats, is essential for regulating the BACE1 cleavage of APP. As the KKRP sequence is known to participate in glycosaminoglycan (GAG) binding, we confirmed that PrPdeltaN did not bind to immobilised heparin. Addition of heparin to SH-SY5Y cells increased the amount of APP cleaved by BACE1 in a concentration-dependent manner and reduced the amount of BACE1 coimmunoprecipitated with PrP, suggesting that GAGs are required for PrP to interact with BACE1 and inhibit APP processing. Of a range of GAGs, including dextran sulphate, hyaluronic acid and chondroitin sulphate, investigated there was complete correlation between those that could restore BACE1 cleavage of APP in PrP expressing cells and those that bound PrP. Conclusion: These data suggest a possible mechanism by which PrP regulates the ßcleavage of APP is through the N-terminus of PrP interacting via GAGs with one or more of the heparin binding sites on BACE1 within a subset of cholesterol-rich lipid rafts, thereby restricting access of BACE1 to APP. Funded by the Medical Research Council of Great Britain.
P04.37
Comparison of the Neuropsychological Profile of Patients with Sporadic Creutzfeldt-Jakob Disease and Patients with Alzheimer’s
Krzovska, M1; Cepek, L1; Ratzka, P2; Döhlinger, S3; Uttner, I1; Wolf, Stefanie4; Irle, Eva4; Mollenhauer, Brit5; Kretzschmar, Hans A.6; Riepe, Matthias7; v. Arnim, Christine1; Otto, Markus1 1University of Ulm, Germany; 2Department of Neurology, Germany; 3University of Goettingen, Germany; 4University of Goettingen, Germany; 5Elena Klinik, Germany; 6LMU, Germany; 7University of Berlin, Germany
Background:To evaluate the neuropsychological profile of sCJD we administered the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) in order to determine if and how the sCJD-Subgroups (Met/Met, Met/Val, Val/Val) have different results in the item analysis of the ADAS-cog. Furthermore, we studied how the scores differ from that of patients with Alzheimer’s disease (AD). Methods:33 sCJD patients (11 with definite CJD and 22 with probable CJD) underwent neuropsychological testing with the ADAS-cog and Mini Mental State Exam (MMSE). Of these 31 were genotyped at the Codon 129 (11 Val/Val, 18 Met/Val and 2 Met/Met). The patients were matched in regards to sex and total ADAS-cog score with AD patients. The scores of the 11 ADAS-cog items were compared between the sCJD and the AD groups as well as between the sCJD-subgroups Met/Val and Val/Val and the AD group. Results:The ADAS-cog total score of the sCJD and AD groups was 22.6+/- 6.5, respectively. Regarding the single Item scores of the sCJD patient group and the AD patient group, there were statistically significant differences in the Items Constructional praxis, Word-finding difficulty in spontaneous speech and Spoken language ability. When comparing the sCJD subtypes with each other no statistically significant difference was found in the items. Conclusion: In the speech domain and constructional praxis there is indication of greater impairment in sCJD patients in general when compared with AD patients. A disturbance of the speech appears to be an important characteristic of the Met/Val and Val/Val subtypes of sCJD, and should therefore be the focus of special attention in future neuropsychological studies.
http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf
please see full text ;
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
http://betaamyloidcjd.blogspot.com/
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
Terry S. Singeltary Sr. P.O. Box 42 Baycliff, Texas USA 77518
Transmission of AA-amyloidosis: Similarities with Prion Disorders
Westermark, P Rudbeck laboratory, Department of Genetics and Pathology, Sweden
The systemic amyloidoses are characterized by widely spread amyloid deposits that can affect virtually every organ in the body. The precursor protein, which varies between different forms is produced at one or several locations, circulates with the plasma and is finally deposited as fibrils in the target organs by mechanisms yet to be determined. In one of the more common forms, systemic AA-amyloidosis, the substrate protein serum AA (SAA) is an acute phase reactant, with significant production only when certain proinflammatory signal substances are upregulated. A persistently high plasma concentration of SAA is a prerequisite for AA-amyloidosis to develop. AA-amyloidosis can easily be induced in many strains of mice by an inflammatory challenge, typically after a long lag phase. This phase is dramatically shortened by administration of amyloid fibrils extracted from an amyloidotic mouse, given intravenously, intra-nasally or given in the drinking water. The fibrillar extract is very potent, active down to pg of protein and facilitates amyloid formation even when given several months before an inflammation is induced. Also amyloid-like fibrils, produced in vitro from synthetic peptides have a clear effect, supporting the idea that the active principle is the misfolded and aggregated protein. AA-amyloidosis occurs in many avian and mammalian species. AA-fibrils from some, but not all species seed murine amyloidosis, showing a species barrier. AA-amyloidosis occurs in species, used as human food and may therefore be a risk factor. Consequently, AA-amyloidosis has similarity with prionoses, differing by the need of an upregulated production of the substrate SAA.
P03.139
Cellular Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein
Hooper, NM1; Parkin, ET1; Watt, NT1; Baybutt, H2; Manson, J2; Hussain, I3; Turner, AJ1 1University of Leeds, Institute of Molecular and Cellular Biology, UK; 2Roslin Institute, Neuropathogenesis Unit, UK; 3GlaxoSmithKline, Neurodegeneration Research, UK
Background: The normal cellular function of the prion protein (PrP), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD) in humans, remains enigmatic. Several studies have reported combinations of Alzheimer’s Disease (AD) and CJD neuropathology and the Val/Met129 polymorphism in the PrP gene has been identified as a risk factor for early-onset AD, leading to speculation that there may be some pathogenic connection between these two neurodegenerative conditions. The amyloid ß (Aß) peptides that cause AD are derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by the ß-secretase (BACE1) and the g-secretase complex. Aim: As both APP and PrP are cleaved by zinc metalloproteases of the ADAM family, we investigated whether PrP alters the proteolytic processing of APP. Results: Here we show that expression of PrP in SH-SY5Y cells dramatically downregulated the cleavage of APP by BACE1 and reduced the secretion of Aß peptides into the conditioned medium by >92%. Conversely, siRNA reduction of endogenous PrP in N2a cells led to an increase in secreted Aß. Furthermore, levels of Aß were significantly increased in the brains of PrP null mice as compared with wild type mice. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases, did not inhibit the BACE1 cleavage of APP. To investigate whether the Val/Met129 polymorphism in human PrPC would alter the production of Aß, brains from mice with the human PrP gene with MM or VV 129 genotypes were analysed. In the MM mice there was a significant increase in Aß in the brains as compared with the VV mice. In the brains of two strains (79A and 87V) of scrapie-infected mice there was a significant increase in Aß peptides as compared to uninfected mice. Conclusions: Together these data reveal a novel function for PrP in regulating the processing of APP through inhibition of BACE1. The increase in APP processing in cells expressing disease-associated forms of PrP and in scrapie-infected brains raises the possibility that the increase in Aß may contribute to the neurodegeneration observed in prion diseases. Funded by the Medical Research Council of Great Britain.
P03.140
Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein through Interaction with Glycosaminoglycans
Griffiths, HH; Parkin, ET; Watt, NT; Turner, AJ; Hooper, NM University of Leeds, Institute of Molecular and Cellular Biology, UK
Background: Proteolytic processing of the amyloid precursor protein (APP) by ßsecretase, BACE1, is the initial step in the production of the amyloid ß (Aß) peptide which is involved in the pathogenesis of Alzheimer’s disease. We have shown that the cellular prion protein (PrP) inhibits the cleavage of APP by BACE1 in cell and animal models. Aim: To investigate the mechanism by which PrP inhibits the action of BACE1. Results: Neither PrPdeltaGPI, which is not membrane attached, nor PrP-CTM, which is anchored by a transmembrane domain and is excluded from cholesterol-rich lipid rafts, reduced cleavage of APP, suggesting that to inhibit the BACE1 cleavage of APP PrP has to be localised to lipid rafts. Coimmunoprecipitation experiments demonstrated that PrP physically interacts with BACE1. However, PrP did not alter the activity of BACE1 towards a fluorogenic peptide substrate nor perturb the dimerisation of BACE1. Using constructs of PrP lacking either the octapeptide repeats or the 4 residues KKRP at the N-terminus of the mature protein (PrPdeltaN), we demonstrate that the KKRP sequence but not the octapeptide repeats, is essential for regulating the BACE1 cleavage of APP. As the KKRP sequence is known to participate in glycosaminoglycan (GAG) binding, we confirmed that PrPdeltaN did not bind to immobilised heparin. Addition of heparin to SH-SY5Y cells increased the amount of APP cleaved by BACE1 in a concentration-dependent manner and reduced the amount of BACE1 coimmunoprecipitated with PrP, suggesting that GAGs are required for PrP to interact with BACE1 and inhibit APP processing. Of a range of GAGs, including dextran sulphate, hyaluronic acid and chondroitin sulphate, investigated there was complete correlation between those that could restore BACE1 cleavage of APP in PrP expressing cells and those that bound PrP. Conclusion: These data suggest a possible mechanism by which PrP regulates the ßcleavage of APP is through the N-terminus of PrP interacting via GAGs with one or more of the heparin binding sites on BACE1 within a subset of cholesterol-rich lipid rafts, thereby restricting access of BACE1 to APP. Funded by the Medical Research Council of Great Britain.
P04.37
Comparison of the Neuropsychological Profile of Patients with Sporadic Creutzfeldt-Jakob Disease and Patients with Alzheimer’s
Krzovska, M1; Cepek, L1; Ratzka, P2; Döhlinger, S3; Uttner, I1; Wolf, Stefanie4; Irle, Eva4; Mollenhauer, Brit5; Kretzschmar, Hans A.6; Riepe, Matthias7; v. Arnim, Christine1; Otto, Markus1 1University of Ulm, Germany; 2Department of Neurology, Germany; 3University of Goettingen, Germany; 4University of Goettingen, Germany; 5Elena Klinik, Germany; 6LMU, Germany; 7University of Berlin, Germany
Background:To evaluate the neuropsychological profile of sCJD we administered the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) in order to determine if and how the sCJD-Subgroups (Met/Met, Met/Val, Val/Val) have different results in the item analysis of the ADAS-cog. Furthermore, we studied how the scores differ from that of patients with Alzheimer’s disease (AD). Methods:33 sCJD patients (11 with definite CJD and 22 with probable CJD) underwent neuropsychological testing with the ADAS-cog and Mini Mental State Exam (MMSE). Of these 31 were genotyped at the Codon 129 (11 Val/Val, 18 Met/Val and 2 Met/Met). The patients were matched in regards to sex and total ADAS-cog score with AD patients. The scores of the 11 ADAS-cog items were compared between the sCJD and the AD groups as well as between the sCJD-subgroups Met/Val and Val/Val and the AD group. Results:The ADAS-cog total score of the sCJD and AD groups was 22.6+/- 6.5, respectively. Regarding the single Item scores of the sCJD patient group and the AD patient group, there were statistically significant differences in the Items Constructional praxis, Word-finding difficulty in spontaneous speech and Spoken language ability. When comparing the sCJD subtypes with each other no statistically significant difference was found in the items. Conclusion: In the speech domain and constructional praxis there is indication of greater impairment in sCJD patients in general when compared with AD patients. A disturbance of the speech appears to be an important characteristic of the Met/Val and Val/Val subtypes of sCJD, and should therefore be the focus of special attention in future neuropsychological studies.
http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf
please see full text ;
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
http://betaamyloidcjd.blogspot.com/
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
Terry S. Singeltary Sr. P.O. Box 42 Baycliff, Texas USA 77518
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