Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
Yvonne S. Eisele,1,2 Ulrike Obermüller,1,2 Götz Heilbronner,1,2,3 Frank Baumann,1,2 Stephan A. Kaeser,1,2
Hartwig Wolburg,4 Lary C. Walker,5 Matthias Staufenbiel,6 Mathias Heikenwalder,7 Mathias Jucker1,2*
1Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen,
Germany. 2DZNE - German Center for Neurodegenerative Diseases, Tübingen, Germany. 3Graduate School for Cellular and
Molecular Neuroscience, University of Tübingen, Tübingen, Germany. 4Department of Pathology, University of Tübingen,
Tübingen, Germany. 5Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA,
USA. 6Novartis Institutes for Biomedical Research, Neuroscience Discovery, Basel, Switzerland. 7Department of Pathology,
Institute for Neuropathology, University Hospital, Zürich, Switzerland.
*To whom correspondence should be addressed. E-mail: mathias.jucker@uni-tuebingen.de
The intracerebral injection of â-amyloid–containing brain extracts can induce cerebral â-amyloidosis and associated pathologies in susceptible hosts. Here, we found that intraperitoneal inoculation with â-amyloid–rich extracts induced â-amyloidosis in the brains of â-amyloid precursor protein transgenic mice after prolonged incubation times.
Intracerebral (i.c.) inoculation with minute amounts of brain extract containing misfolded ß-amyloid (Aß) from patients with Alzheimer’s Disease or from amyloid-bearing ß-amyloid precursor protein (APP) transgenic (tg) mice induces cerebral ß-amyloidosis and related pathologies in APP tg mice in a time- and concentration-dependent manner (1). However, oral, intravenous, intraocular, or intranasal inoculations have failed to induce cerebral ß-amyloidosis in APP tg hosts (2). These findings suggest that Aß-containing brain material in direct contact with the brain can induce cerebral ß-amyloidosis, but that, unlike prions, either the inducing agent is not readily conveyed from peripheral sites to the brain, or a higher concentration or longer incubation period is required for peripherally delivered Aß seeds.
Intraperitoneal (i.p.) administration of prion-rich material is more efficient at transmitting prion disease than is oral administration (3, 4). To test whether i.p. inoculation of Aß- rich material might similarly trigger Aß misfolding and deposition in the brain, we administered two i.p. injections (100 µl each, 1 week apart) of Aß-laden (10-20 ng/µl) brain extract from aged APP23 tg mice (Tg extract) to a cohort of young (2-month-old) female APP23 tg mice (5). After a 7-month incubation period, cerebral ß-amyloidosis was robustly induced in all i.p. inoculated mice compared to untreated littermate controls (Fig. 1). To confirm this finding, we inoculated a second cohort of 2-month-old female APP23 mice with a different batch of Tg brain extract in another laboratory (cohort 2: Tübingen, vs. cohort 1: Basel). After 6–7 months, mice injected i.p. with the Tg extract exhibited robust cerebral ß-amyloidosis, whereas i.p. inoculation with phosphate-buffered saline (PBS) or brain extract from agematched, non-tg wildtype mice (Wt extract) was ineffective (Fig. 1).
Induced ß-amyloidosis was strongest in the anterior and entorhinal cortices with additional deposition in the hippocampus, resembling the regional development of endogenous ß-amyloidosis in aged APP23 mice (6). However, whereas normal aged APP23 mice manifest mostly parenchymal deposits, the induced ß-amyloid in i.p. seeded mice was predominantly associated with blood vessels (cerebral ß-amyloid angiopathy [Aß-CAA]), often with massive spreading into the neighboring brain parenchyma (Fig. 1). The presence of Aß was confirmed by immunoblotting, and amyloid fibrils were evident ultrastructurally; in addition, the induced ß-amyloidosis was linked to gliosis, hyperphosphorylated tau, and other associated pathologies (Fig. 2), reminiscent of the cerebral ß-amyloid deposition in aged APP23 mice (6, 7).
To compare the efficiency and time course of i.p. versus i.c. inoculation, 2-month-old female APP23 mice were inoculated either i.p. (2 x 100 µl) or i.c. (2.5 µl into the hippocampus) with Tg extract, and then analyzed 4 months later. No cerebral ß-amyloid induction was found in any of the 4 i.p. inoculated mice, while all 6 i.c. inoculated mice revealed ß-amyloid induction identical to that previously reported (1, 2). From this observation, together with previous time course and 1:20 dilution experiments for i.c. inoculations (1), we estimate that i.p. inoculations with 103-fold more Aß take 2–5 months longer to induce cerebral ß-amyloidosis than do i.c. inoculations.
The replication of peripherally applied prions and their translocation into the central nervous system depend on hematopoietic and stromal immune cells, in combination with sympathetic innervation of abdominal lymphoid organs (8). Both activation of the immune system and chronic inflammation promote prion replication (9, 10). To assess the immune response to Aß-rich brain extracts, additional APP23 mice were given single i.p. injections of 200 µl Tg or Wt extract and sacrificed 1 hour, 1 week, or 1 month postinjection (5). An acute immune activation to the injected brain material was indicated by transient increases in plasma chemokines and cytokines (IL6, IL10, TNF-a, MCP-1, MIP-1ß) in both Tg and Wt extract-inoculated mice after 1 hour, with IL-6 still mildly elevated in Tg extract-injected mice 1 week post-inoculation (fig. S1). However, no signs of chronic inflammation in various peripheral organs (e.g. liver,pancreas, kidney, lung) or serum anti-Aß antibody titers were found in any mice investigated at 1 or 7 months postseeding (5). Moreover, no ß-amyloid deposition was found in any of the peripheral tissues at any time point studied.
Thus, like prion disease, cerebral ß-amyloidosis can be seeded in the brain by homologous protein aggregates delivered into the peritoneal cavity, although the i.p. route required more time and was less efficient than was direct injection into the brain (1, 2). The amyloid-inducing factor in the Tg extract is probably a species of misfolded Aß that is generated in its most effective form or composition in vivo (1). Because the expression of tg (human) APP is restricted to the nervous system in APP23 mice (7), in this model it is likely that the seed carried to the brain was the injected material itself, rather than Aß aggregates that were first amplified in peripheral tissues.
There is now persuasive evidence that the aggregation of Aß is a key pathogenic feature of AD and Aß-CAA (11–14), although the majority of these cases are initiated by unknown causes. The possibility that mechanisms exist allowing for the transport of Aß aggregates (and possibly other seeds) from the periphery to the brain justifies further studies to better understand the cellular and molecular origin of these diseases and to clarify the basis of infectious vs. non-infectious proteopathies (15, 16).
References and Notes
References and Notes
1. M. Meyer-Lühmann et al., Science 131, 1781 (2006).
2. Y. S. Eisele et al., Proc Natl Acad Sci USA 106, 12926
(2009).
3. S.B. Prusiner, Prion Biology and Diseases (Cold Spring
Harbor Laboratory Press), 2nd Ed pp. 1050 (2004).
4. R.H. Kimberlin, C.A. Walker, J Comp Path 88, 39 (1978).
5. For methods, see Supporting Online Material.
6. C. Sturchler-Pierrat et al., Proc Natl Acad Sci USA 94,
13287 (1997).
7. M.E. Calhoun et al., Proc Natl Acad Sci USA 96, 14088
(1999).
8. A. Aguzzi, C. Sigurdson, M. Heikenwälder, Ann Rev
Pathol Mech Dis 3, 11 (2008).
9. M. Heikenwalder et al., Science 307, 1107 (2005).
10. J. Bremer et al., PloS One 4, e7160 (2009).
11. J. Hardy, D. J. Selkoe, Science 297, 353 (2002).
12. M. Sorandt, M. A. Mintun, D. Head, J. C. Morris, Arch
Neurol 66, 1476 (2009).
13. J. C. Morris et al., Arch Neurol 66, 1469 (2009).
14. S. X. Zhang-Nunes et al., Brain Pathology 16, 30 (2006).
15. L. C. Walker, H. LeVine, M. P. Mattson, M. Jucker,
Trends Neurosci 29, 438 (2006).
16. A. Aguzzi, L. Rajendran, Neuron 64, 783 (2009).
17. We thank M.-J. Runser, L. Jacobson (Basel), F. Langer, J.
Coomaraswamy, S. Grathwohl, N. Varvel, T. Hamaguchi,
C. Schäfer, A. Bosch, G. Frommer-Kästle, U. Scheurlen
(Tübingen) for experimental help and A. Aguzzi (Zürich)
for insightful comments. Supported by the Competence
Network on Degenerative Dementias (BMBF-01GI0705),
the BMBF in the frame of ERA-Net NEURON
(MIPROTRAN), the CIN (DFG), and NIH RR-00165.
Supporting Online Material
www.sciencemag.org/cgi/content/full/science.1194516/DC1
Materials and Methods
Fig. S1
References
1 July 2010; accepted 24 September 2010
Published online 21 October 2010; 10.1126/science.1194516
Fig. 1. Induced Aß deposition. (A and B) Aß-immunostained frontal cortex of Tg extract- (A) and Wt extract- (B) i.p. inoculated APP23 mice. (C and D) Most induced ß-amyloid was vascular (Aß-CAA), with Aß-immunoreactivity extending into the brain parenchyma (arrows). Amyloid-laden vessels were congophilic (red in D; birefringent under crosspolarized light, insert) and often were surrounded by diffuse, Congo red-negative Aß deposits (arrowheads). (E and F) Analysis of the entire neocortex for Aß-CAA frequency (indicated are all three [I-III] CAA severity grades [5]), and for total Aß load in Tg extract-inoculated mice compared to control (Ctr) mice. Cohort 1 consisted of 6 Tg extractinoculated mice vs. 7 untreated control mice. Aß-CAA: t(11) = 6.78 (all severity grades combined), ***P < 0.0001; Aß load: t(11) = 8.79, ***P < 0.0001. Cohort 2 consisted of 5 Tg extract-inoculated mice vs. 5 Wt extract-inoculated mice and 4 PBS-injected mice. These latter 2 (control) groups did not differ significantly, and were combined for analysis. Aß-CAA: t(12) = 7.79, ***P < 0.0001; Aß load t(12) = 2.71, *P < 0.05. The occasional parenchymal Aß-deposits in control mice are normal for 9-month-old APP23 mice. Indicated are means ±SEM. Scale bars: 200 µm (A,B); 50 µm (C,D).
Fig. 2. Induced Aß deposition was linked to multiple associated pathologies. (A) Ultrastructural analysis showed amyloid deposition within the vascular basal lamina (BL), with typical amyloid fibrils (arrowheads) extending into the brain parenchyma. Insets are low- and high-magnification views of the examined vessel (L = lumen) and the typical non-branching amyloid fibrils. (B to E) Vascular amyloid(stained by Congo Red in B and C) and parenchymal plaques were surrounded by hypertrophic, Iba1-positive microglia (B), GFAP-positive astrocytes (C), hyperphosphorylated taupositive neurites (D; asterisk indicates amyloid core), but a paucity of proximate neurons (cresyl-violet stain, E). (F and G) Vessels with CAA types II and III showed smooth muscle cell loss at the site of amyloid deposition (arrowheads; confocal image, maximum projection of 5 µm z-stack: red, Aß; green, smooth muscle actin). A normal vessel (G) has a complete ring of smooth muscle cells. (H) Immunoblotting of micropunches of Aß-immunoreactive material revealed the expected Aß band. Synthetic Aß40/42 is shown as control. Markers = 3 and 6 kD. Scale bars: 1 µm (A; insets 5 and 0.5 µm); 50 µm (B-E); 10 µm (F, G).
end...see ;
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
http://www.sciencemag.org/cgi/content/abstract/science.1194516
BSE101/1 0136
IN CONFIDENCE
CMO
From: Dr J S Metters DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
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
http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html
http://betaamyloidcjd.blogspot.com/
2010 PRION UPDATE
Thursday, August 12, 2010
Seven main threats for the future linked to prions
http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html
http://prionpathy.blogspot.com/
TSS
Showing posts with label Prionoids. Show all posts
Showing posts with label Prionoids. Show all posts
Friday, October 22, 2010
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
Sunday, August 8, 2010
The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
http://betaamyloidcjd.blogspot.com/2010/08/transcellular-spread-of-cytosolic.html
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
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://www.seac.gov.uk/pdf/hol-response091008.pdf
see full text and more science on this topic here ;
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
13
Simultaneous Onset of Alzheimer's Disease in a Husband and Wife in Their Mid Fifties: What do We Really Know?
Jonathan Heath1, Lindsay Goicochea2, Mark Smith3, Rudy Castellani4. 1Department of Pathology, University of Maryland; 2University; 3Case Western Reserve University; 4University of Maryland, Baltimore, Maryland
Whereas the genetic factors influencing the development and expression of Alzheimer's disease are well characterized, environmental factors are currently thought to play a marginal role. Such factors as prior closed head injury, post-menopausal estrogen deficiency, aluminum exposure, smoking, diabetes, atherosclerotic cardiovascular disease, and diet, among others, confer only a modest increased risk if any, and are only tangentially considered in the major pathogenic cascades that are presently hypothesized. We present the simultaneous onset of Alzheimer's disease in a husband and wife, with both subjects experiencing cognitive dysfunction within the same month. Both subjects were in their mid-fifties at the time of presentation, both subjects showed progressively neurological decline with prominent memory loss, both subjects experienced myoclonus late in their disease course prompting referral to the National Prion Disease Pathology Surveillance Center, and both subjects expired 12 years after onset, within two months of each other. Review of the family pedigree revealed no family history of dementia or other neurologic illnesses in multiple first degree relatives. The only historical finding of note was that both subjects had moved out of their home briefly while it was being remodeled, and both became symptomatic shortly after moving back in. At autopsy, the subjects had classic advanced Alzheimer's disease, with Braak stage VI pathology that was otherwise identiical in quantity and distribution of amyloid-beta, cerebral amyloid angiopathy, and neurofibrillary degeneration. While no specific toxin or other environmental cause was discerned, these two cases raise the issue of epigenetic factors in Alzheimer's disease that may be more robust than current literature indicates.
http://journals.lww.com/jneuropath/Fulltext/2010/05000/American_Association_of_Neuropathologists,_Inc__.9.aspx
NEUROLOGY 1998;50:684-688 © 1998 American Academy of Neurology
Creutzfeldt-Jakob disease in a husband and wife
P. Brown, MD, L. Cervenáková, MD, L. McShane, PhD, L. G. Goldfarb, MD, K. Bishop, BS, F. Bastian, MD, J. Kirkpatrick, MD, P. Piccardo, MD, B. Ghetti, MD and D. C. Gajdusek, MD From the Laboratory of CNS Studies (Drs. Brown, Cervenáková, Goldfarb, and Gajdusek), NINDS, and Biometric Research Branch (Dr. McShane), NCI, National Institutes of Health, Bethesda, MD; the Department of Obstetrics (K. Bishop), Gynecology and Reproductive Sciences, University of Texas Houston Health Science Center, Houston, TX; the Department of Pathology (Dr. Bastian), University of South Alabama Medical Center, Mobile, AL; the Department of Pathology (Dr. Kirkpatrick), The Methodist Hospital, Houston, TX; and the Department of Pathology (Drs. Piccardo and Ghetti), Indiana University School of Medicine, Indianapolis, IN.
Address correspondence and reprint requests to Dr. Paul Brown, Building 36, Room 5B21, National Institutes of Health, Bethesda, MD 20892.
A 53-year-old man died of sporadic Creutzfeldt-Jakob disease (CJD) after a 1.5-year clinical course. Four and a half years later, his then 55-year-old widow died from CJD after a 1-month illness. Both patients had typical clinical and neuropathologic features of the disease, and pathognomonic proteinase-resistant amyloid protein ("prion" protein, or PrP) was present in both brains. Neither patient had a family history of neurologic disease, and molecular genetic analysis of their PrP genes was normal. No medical, surgical, or dietary antecedent of CJD was identified; therefore, we are left with the unanswerable alternatives of human-to-human transmission or the chance occurrence of sporadic CJD in a husband and wife.
--------------------------------------------------------------------------------
Received May 5, 1997. Accepted in final form September 10, 1997.
http://www.neurology.org/cgi/content/abstract/50/3/684
Research Lead: Dr. David Westaway, University of Alberta
Project: "Extending the spectrum of Prionopathies to Amyotrophic Lateral Sclerosis and Autism"
This project proposes to link the chemistry of the prion protein to the new territory of other nervous system diseases, such as ALS (Lou Gehrig's disease) and the socialization disorder autism-diseases which are at least one thousand times more common than prion diseases. It is believed that a different type or prion protein may operate in other types of brain diseases, which could lead to new ways of thinking about incurable disorders. The project will create changes in the amounts of the various forms of the new membrane protein, and then perform an array of analyses on the behavior and nervous system transmission of laboratory mice. Nervous transmission by electrical impulse can be measured in isolated brain cells, a system that is also convenient to study the effect of stress by adding small amounts of toxins to the fluids bathing the cultures. By these means, the project aims to extend the boundaries of what is considered "prion disease."
Funding: $520,500
http://www.prioninstitute.ca/index.php?page=webpages&menucat=42&id=26&action=displaypage&side=1
Unfolding the Prion Mystery Building and Growing Research Expertise in Alberta Year 4 2008-2009 Annual Report
Dr. David Westaway, University of Alberta Extending the spectrum of prionopathies to amyotrophic lateral sclerosis (ALS) and autism Dr. Westaway’s study aims to extend the boundaries of what is considered prion disease. His project takes the chemistry of the prion protein into the territory of nervous system diseases such as ALS (Lou Gehrig’s disease) and socialization disorder diseases such as autism. These brain diseases are at least 1,000 times more common than diseases currently accepted as prion related. Dr. Westaway hypothesizes that a different type of protein misfolding may operate in brain diseases such as Lou Gehrig’s and autism. This type of protein misfolding may occur in response to stresses in the brain. Unlike misfolded prions, other misfolded proteins may be noninfectious and not viable outside of the affected animal. Dr. Westaway’s research team will investigate these hypotheses by inducing changes in the brain cells of laboratory mice, measuring the resulting electrical impulses in the animals’ nervous systems and analyzing the effect on behaviour. Because nervous transmission by electrical impulse can be measured in isolated brain cells, adding small amounts of toxins to the fluids bathing the cell cultures will make it possible to study the effect of stress. The results could lead to new ways of thinking about nervous system disorders.
http://www.prioninstitute.ca/forms/WEBSITE%20AR.pdf
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
TWA LITTLE STATEMENT 331
http://collections.europarchive.org/tna/20080102163939/http://www.bseinquiry.gov.uk/files/ws/s331.pdf
http://collections.europarchive.org/tna/20080103032631/http://www.bseinquiry.gov.uk/files/yb/1988/11/04003001.pdf
8. The Secretary of State has a number of licences. We understand that the inactivated polio vaccine is no longer being used. There is a stock of smallpox vaccine. We have not been able to determine the source material. (Made in sheep very unlikely to contain bovine ingredients).
CONFIDENTIAL
http://collections.europarchive.org/tna/20080102164642/http://www.bseinquiry.gov.uk/files/yb/1989/02/14010001.pdf
see full text ;
http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html
Terry S. Singeltary Sr. [flounder@wt.net]
Monday, January 08,200l 3:03 PM
freas@CBS5055530.CBER.FDA.GOV CJD/BSE (aka madcow) Human/Animal TSE’s --U.S.-- Submission To Scientific Advisors and Consultants Staff January 2001 Meeting (short version)
Greetings again Dr. Freas and Committee Members,
http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
BELOW, PAGE 1 ACTUALLY STARTS ON PAGE 13, then when you get to the bottom, part 3 starts at the top.........TSS
From: Terry S. Singeltary Sr.
To: FREAS@CBER.FDA.GOV
Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov
Sent: Friday, December 01, 2006 2:59 PM
Subject: Re: TSE advisory committee for the meeting December 15, 2006 [TSS SUBMISSION
snip...
ONE FINAL COMMENT PLEASE, (i know this is long Dr. Freas but please bear with me)
THE USA is in a most unique situation, one of unknown circumstances with human and animal TSE. THE USA has the most documented TSE in different species to date, with substrains growing in those species (BSE/BASE in cattle and CWD in deer and elk, there is evidence here with different strains), and we know that sheep scrapie has over 20 strains of the typical scrapie with atypical scrapie documented and also BSE is very likely to have passed to sheep. all of which have been rendered and fed back to animals for human and animal consumption, a frightening scenario. WE do not know the outcome, and to play with human life around the globe with the very likely TSE tainted blood from the USA, in my opinion is like playing Russian roulette, of long duration, with potential long and enduring consequences, of which once done, cannot be undone.
These are the facts as i have come to know through daily and extensive research of TSE over 9 years, since 12/14/97. I do not pretend to have all the answers, but i do know to continue to believe in the ukbsenvcjd only theory of transmission to humans of only this one strain from only this one TSE from only this one part of the globe, will only lead to further failures, and needless exposure to humans from all strains of TSE, and possibly many more needless deaths from TSE via a multitude of proven routes and sources via many studies with primates and rodents and other species. ...
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
snip... 48 pages...
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=09000064801f3413&disposition=attachment&contentType=msw8
Subject: Louping-ill vaccine documents from November 23rd, 1946
Date: Sat, 9 Sep 2000 17:44:57 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
http://www.whale.to/v/singeltary.html
Tuesday, August 03, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?
http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Wednesday, August 18, 2010
Incidence of CJD Deaths Reported by CJD-SS in Canada as of July 31, 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/incidence-of-cjd-deaths-reported-by-cjd.html
Monday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)
(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)
http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html
TSS
Sunday, August 8, 2010
The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
http://betaamyloidcjd.blogspot.com/2010/08/transcellular-spread-of-cytosolic.html
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
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://www.seac.gov.uk/pdf/hol-response091008.pdf
see full text and more science on this topic here ;
http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html
13
Simultaneous Onset of Alzheimer's Disease in a Husband and Wife in Their Mid Fifties: What do We Really Know?
Jonathan Heath1, Lindsay Goicochea2, Mark Smith3, Rudy Castellani4. 1Department of Pathology, University of Maryland; 2University; 3Case Western Reserve University; 4University of Maryland, Baltimore, Maryland
Whereas the genetic factors influencing the development and expression of Alzheimer's disease are well characterized, environmental factors are currently thought to play a marginal role. Such factors as prior closed head injury, post-menopausal estrogen deficiency, aluminum exposure, smoking, diabetes, atherosclerotic cardiovascular disease, and diet, among others, confer only a modest increased risk if any, and are only tangentially considered in the major pathogenic cascades that are presently hypothesized. We present the simultaneous onset of Alzheimer's disease in a husband and wife, with both subjects experiencing cognitive dysfunction within the same month. Both subjects were in their mid-fifties at the time of presentation, both subjects showed progressively neurological decline with prominent memory loss, both subjects experienced myoclonus late in their disease course prompting referral to the National Prion Disease Pathology Surveillance Center, and both subjects expired 12 years after onset, within two months of each other. Review of the family pedigree revealed no family history of dementia or other neurologic illnesses in multiple first degree relatives. The only historical finding of note was that both subjects had moved out of their home briefly while it was being remodeled, and both became symptomatic shortly after moving back in. At autopsy, the subjects had classic advanced Alzheimer's disease, with Braak stage VI pathology that was otherwise identiical in quantity and distribution of amyloid-beta, cerebral amyloid angiopathy, and neurofibrillary degeneration. While no specific toxin or other environmental cause was discerned, these two cases raise the issue of epigenetic factors in Alzheimer's disease that may be more robust than current literature indicates.
http://journals.lww.com/jneuropath/Fulltext/2010/05000/American_Association_of_Neuropathologists,_Inc__.9.aspx
NEUROLOGY 1998;50:684-688 © 1998 American Academy of Neurology
Creutzfeldt-Jakob disease in a husband and wife
P. Brown, MD, L. Cervenáková, MD, L. McShane, PhD, L. G. Goldfarb, MD, K. Bishop, BS, F. Bastian, MD, J. Kirkpatrick, MD, P. Piccardo, MD, B. Ghetti, MD and D. C. Gajdusek, MD From the Laboratory of CNS Studies (Drs. Brown, Cervenáková, Goldfarb, and Gajdusek), NINDS, and Biometric Research Branch (Dr. McShane), NCI, National Institutes of Health, Bethesda, MD; the Department of Obstetrics (K. Bishop), Gynecology and Reproductive Sciences, University of Texas Houston Health Science Center, Houston, TX; the Department of Pathology (Dr. Bastian), University of South Alabama Medical Center, Mobile, AL; the Department of Pathology (Dr. Kirkpatrick), The Methodist Hospital, Houston, TX; and the Department of Pathology (Drs. Piccardo and Ghetti), Indiana University School of Medicine, Indianapolis, IN.
Address correspondence and reprint requests to Dr. Paul Brown, Building 36, Room 5B21, National Institutes of Health, Bethesda, MD 20892.
A 53-year-old man died of sporadic Creutzfeldt-Jakob disease (CJD) after a 1.5-year clinical course. Four and a half years later, his then 55-year-old widow died from CJD after a 1-month illness. Both patients had typical clinical and neuropathologic features of the disease, and pathognomonic proteinase-resistant amyloid protein ("prion" protein, or PrP) was present in both brains. Neither patient had a family history of neurologic disease, and molecular genetic analysis of their PrP genes was normal. No medical, surgical, or dietary antecedent of CJD was identified; therefore, we are left with the unanswerable alternatives of human-to-human transmission or the chance occurrence of sporadic CJD in a husband and wife.
--------------------------------------------------------------------------------
Received May 5, 1997. Accepted in final form September 10, 1997.
http://www.neurology.org/cgi/content/abstract/50/3/684
Research Lead: Dr. David Westaway, University of Alberta
Project: "Extending the spectrum of Prionopathies to Amyotrophic Lateral Sclerosis and Autism"
This project proposes to link the chemistry of the prion protein to the new territory of other nervous system diseases, such as ALS (Lou Gehrig's disease) and the socialization disorder autism-diseases which are at least one thousand times more common than prion diseases. It is believed that a different type or prion protein may operate in other types of brain diseases, which could lead to new ways of thinking about incurable disorders. The project will create changes in the amounts of the various forms of the new membrane protein, and then perform an array of analyses on the behavior and nervous system transmission of laboratory mice. Nervous transmission by electrical impulse can be measured in isolated brain cells, a system that is also convenient to study the effect of stress by adding small amounts of toxins to the fluids bathing the cultures. By these means, the project aims to extend the boundaries of what is considered "prion disease."
Funding: $520,500
http://www.prioninstitute.ca/index.php?page=webpages&menucat=42&id=26&action=displaypage&side=1
Unfolding the Prion Mystery Building and Growing Research Expertise in Alberta Year 4 2008-2009 Annual Report
Dr. David Westaway, University of Alberta Extending the spectrum of prionopathies to amyotrophic lateral sclerosis (ALS) and autism Dr. Westaway’s study aims to extend the boundaries of what is considered prion disease. His project takes the chemistry of the prion protein into the territory of nervous system diseases such as ALS (Lou Gehrig’s disease) and socialization disorder diseases such as autism. These brain diseases are at least 1,000 times more common than diseases currently accepted as prion related. Dr. Westaway hypothesizes that a different type of protein misfolding may operate in brain diseases such as Lou Gehrig’s and autism. This type of protein misfolding may occur in response to stresses in the brain. Unlike misfolded prions, other misfolded proteins may be noninfectious and not viable outside of the affected animal. Dr. Westaway’s research team will investigate these hypotheses by inducing changes in the brain cells of laboratory mice, measuring the resulting electrical impulses in the animals’ nervous systems and analyzing the effect on behaviour. Because nervous transmission by electrical impulse can be measured in isolated brain cells, adding small amounts of toxins to the fluids bathing the cell cultures will make it possible to study the effect of stress. The results could lead to new ways of thinking about nervous system disorders.
http://www.prioninstitute.ca/forms/WEBSITE%20AR.pdf
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
TWA LITTLE STATEMENT 331
http://collections.europarchive.org/tna/20080102163939/http://www.bseinquiry.gov.uk/files/ws/s331.pdf
http://collections.europarchive.org/tna/20080103032631/http://www.bseinquiry.gov.uk/files/yb/1988/11/04003001.pdf
8. The Secretary of State has a number of licences. We understand that the inactivated polio vaccine is no longer being used. There is a stock of smallpox vaccine. We have not been able to determine the source material. (Made in sheep very unlikely to contain bovine ingredients).
CONFIDENTIAL
http://collections.europarchive.org/tna/20080102164642/http://www.bseinquiry.gov.uk/files/yb/1989/02/14010001.pdf
see full text ;
http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html
Terry S. Singeltary Sr. [flounder@wt.net]
Monday, January 08,200l 3:03 PM
freas@CBS5055530.CBER.FDA.GOV CJD/BSE (aka madcow) Human/Animal TSE’s --U.S.-- Submission To Scientific Advisors and Consultants Staff January 2001 Meeting (short version)
Greetings again Dr. Freas and Committee Members,
http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
BELOW, PAGE 1 ACTUALLY STARTS ON PAGE 13, then when you get to the bottom, part 3 starts at the top.........TSS
From: Terry S. Singeltary Sr.
To: FREAS@CBER.FDA.GOV
Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov
Sent: Friday, December 01, 2006 2:59 PM
Subject: Re: TSE advisory committee for the meeting December 15, 2006 [TSS SUBMISSION
snip...
ONE FINAL COMMENT PLEASE, (i know this is long Dr. Freas but please bear with me)
THE USA is in a most unique situation, one of unknown circumstances with human and animal TSE. THE USA has the most documented TSE in different species to date, with substrains growing in those species (BSE/BASE in cattle and CWD in deer and elk, there is evidence here with different strains), and we know that sheep scrapie has over 20 strains of the typical scrapie with atypical scrapie documented and also BSE is very likely to have passed to sheep. all of which have been rendered and fed back to animals for human and animal consumption, a frightening scenario. WE do not know the outcome, and to play with human life around the globe with the very likely TSE tainted blood from the USA, in my opinion is like playing Russian roulette, of long duration, with potential long and enduring consequences, of which once done, cannot be undone.
These are the facts as i have come to know through daily and extensive research of TSE over 9 years, since 12/14/97. I do not pretend to have all the answers, but i do know to continue to believe in the ukbsenvcjd only theory of transmission to humans of only this one strain from only this one TSE from only this one part of the globe, will only lead to further failures, and needless exposure to humans from all strains of TSE, and possibly many more needless deaths from TSE via a multitude of proven routes and sources via many studies with primates and rodents and other species. ...
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
snip... 48 pages...
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=09000064801f3413&disposition=attachment&contentType=msw8
Subject: Louping-ill vaccine documents from November 23rd, 1946
Date: Sat, 9 Sep 2000 17:44:57 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
http://www.whale.to/v/singeltary.html
Tuesday, August 03, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?
http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Wednesday, August 18, 2010
Incidence of CJD Deaths Reported by CJD-SS in Canada as of July 31, 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/incidence-of-cjd-deaths-reported-by-cjd.html
Monday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)
(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)
http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html
TSS
Sunday, August 8, 2010
The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
Neuron
Perspective
The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
Adriano Aguzzi1,* and Lawrence Rajendran2,* 1Institute of Neuropathology, University Hospital of Zu¨ rich, Schmelzbergstrasse 12, CH-8091 Zu¨ rich, Switzerland 2Systems and Cell Biology of Neurodegeneration, Psychiatry Research, University of Zurich, CH-8008 Zu¨ rich, Switzerland *Correspondence: adriano.aguzzi@usz.ch (A.A.), rajendran@bli.uzh.ch (L.R.) DOI 10.1016/j.neuron.2009.12.016
Recent reports indicate that a growing number of intracellular proteins are not only prone to pathological aggregation but can also be released and ‘‘infect’’ neighboring cells. Therefore, many complex diseases may obey a simple model of propagation where the penetration of seeds into hosts determines spatial spread and disease progression. We term these proteins prionoids, as they appear to infect their neighbors just like prions—but how can bulky protein aggregates be released from cells and how do they access other cells? The widespread existence of such prionoids raises unexpected issues that question our understanding of basic cell biology.
Imagine that you are a neuroscientist vacationing on Mars. One day you encounter a colony of Martians that, as it happens, look similar to water bottles. The Martians are highly distressed and seek your advice, as their community is plagued by an enigmatic transmissible disease. Intrigued, you agree to help. It turns out that the bodies of your exobiotic friends consist of bottles filled with a supersaturated salt solution. At some point crystals have started forming in one individual, and then crystallization has somehow been transferred to other community members. Lacking molecular insight, you would initially conclude that the Martians are affected by an infectious agent. Through ingenuity and technology, you may then discover that the infectious agent is exceedingly simple and homogeneous, that it lacks informational nucleic acids, and that it is generated both by ordered aggregation of an intrinsic precursor and by appositional growth of extrinsically added seeds. Your discovery will earn you the Intergalactic Nobel Prize, yet two crucial questions remain unanswered: how do the crystals transfer between individuals, and what can be done to prevent this from happening?
Middle-aged readers may feel reminded of the plot for Andromeda Strain, a stunningly prescient novel published in 1969 by the late Michael Crichton. But the sci-fi scenario described above is also the blueprint of Prusiner’s hypothesis of prion propagation. Over time, we have learned that prions consist of PrPSc, higher-order aggregates of a physiological protein termed PrPC. Accordingly, prions propagate through elongation and breakage of PrPSc aggregates (Aguzzi and Polymenidou, 2004)—not unlike the crystals vexing our extraterrestrial friends.
There is mounting evidence (Clavaguera et al., 2009; Frost et al., 2009; Ren et al., 2009; Desplats et al., 2009; Luk et al., 2009) suggesting that the events sketched above, far from being confined to science-fiction and prion diseases (whose incidence in humans is just z1/106/year), may underlie highly prevalent human diseases of the brain and many other organs. The unifying characteristics of all these diseases is the aggregation of proteins into highly ordered stacks, henceforth termed ‘‘amyloids’’ irrespective of their size. Since PrPSc undoubtedly fulfills the latter definition of amyloid, one is led to wonder whether the prion principle may be much more pervasive than previously appreciated and whether many more diseases of unknown cause may eventually turn out to rely on prion-like propagation (Table 1, upper panel). Even more intriguingly, a number of proteins appear to exert normal functions when arranged in highly ordered stacks that are similar to amyloids and to prionoids (Table 1, lower panel).
Prions and Prionoids
There is one crucial difference between bona fide prion diseases and all other amyloids and prion-like phenomena hitherto described in uni- and pluricellular organisms (Table 1). Prions are infectious agents, transmissible between individuals, and tractable with microbiological techniques—including, e.g., titer determinations. Even if certain amyloids of yeast and mammals appear to infect neighboring molecules and sometimes neighboring cells, they do not propagate within communities, and none of them were found to cause macroepidemics such as Kuru and bovine spongiform encephalopathy. We have therefore termed these self-aggregating proteins ‘‘prionoids’’ (Aguzzi, 2009), since the lack of microbiological transmissibility precludes their classification as true prions.
Some prionoids may soon qualify for an upgrade to prion status. At least in select settings, amyloid A (AA) amyloidosis may exist as a truly infectious disease based on a self-propagating protein. AA amyloid consists of orderly aggregated fragments of SAA protein, whose deposition can damage many organs of the body. Somewhat bizarrely, AA aggregation is also present in the liver of force-fed geese, hence contributing to the pathophysiology of foie gras (Solomon et al., 2007). AA seeds can induce amyloidosis upon transfer of white blood cells (Sponarova et al., 2008). Furthermore, AA seeds are excreted with the feces, and AA amyloidosis is endemic in populations of cheetah (Zhang et al., 2008). It is therefore tantalizing to suspect that amyloid may entertain the complete life cycle of an infectious agent, including transmission by the orofecal and hematogenous route—similarly to enteroviruses and, perhaps, scrapie prions. While there may be many other good reasons to avoid foie gras, including, e.g., animal welfare concerns, gourmets may not need to panic: under experimental conditions, AA amyloidosis is only transmitted to AgNO3-pretreated mice that display elevated levels of the SAA precursor protein.
Alzheimer’s disease (AD) has long been suspected to be a transmissible disease, but these suspicions have never materialized in epidemiological studies. On the other hand, Mathias Jucker and Lary Walker observed that injection of the Ab peptide from human AD brains induced robust and convincing aggregation of Ab in transgenic mice overexpressing the Ab precursor protein, APP (Kane et al., 2000; Meyer-Luehmann et al., 2006). Jucker’s finding raises an epistemologically significant question: if aggregation depends on the introduction of seeds and on the availability of the monomeric precursor, and if amyloid represents the primordial state of all proteins (Chiti and Dobson, 2006), wouldn’t all proteins—under appropriate conditions— give rise to prionoids in the presence of sufficient precursor?
The issues sketched above go well beyond AD and prions. There are many other diseases—not necessarily involving the nervous system—whose pathogenesis involves ordered aggregation of proteins, but for which there is no evidence of transmission between individuals. The best-studied of these are the systemic amyloidoses, which come about through the nucleation of some aggregation-prone proteins such as transthyretin and immunoglobulin light chains. Yet ordered protein aggregation is by no means confined to the ‘‘classical’’ amyloidoses and extends to a number of conditions, some of which have been rather unexpected.
Type II diabetes is yet another disease whose pathogenesis may involve ordered protein aggregation. Evidence to support this idea was discovered over a century ago (Opie, 1901) but was largely forgotten until recently. It is now evident that aggregation of islet amyloid polypeptide (IAPP) is an exceedingly frequent feature of type II diabetes. IAPP amyloids damage the insulin-producing b cells within pancreatic islets and may crucially contribute to the pathogenesis of diabetes (Hull et al., 2004). It is unknown, however, whether IAPP deposition simply accrues linearly with IAPP production or whether it spreads prion-like from one pancreatic islet to the next.
A body of recent work supports the idea that many aggregation proteinopathies are, in one way or another, transmissible. A recent report showed that a-synuclein is released from neurons and is then taken up by the neighboring cells, thereby aiding in a progressive spread of the protein (Desplats et al., 2009; Lee et al., 2005). When exogenously added to cultured cells, fluorescently labeled, recombinant a-synuclein was internalized from the extracellular milieu into the cytosol. Furthermore, injection of GFP-labeled mouse cortical neuronal stem cells into the hippocampus of a-synuclein-transgenic mice led to the efficient uptake of the host a-synuclein into the grafted cells after just 4 weeks. These findings are reminiscent of the observation that healthy fetal tissue, grafted into the brains of Parkinson’s disease patients, acquired intracellular Lewy bodies. The latter phenomenon is somewhat anecdotal and has been disputed (Mendez et al., 2008), yet it would be entirely compatible with the hypothesis that a-synuclein aggregates are prionoids (Li et al., 2008). A similar study conclusively demonstrated that exogenous a-synuclein fibrils induced the formation of Lewy body-like intracellular inclusions in vitro (Luk et al., 2009). This study also showed that the conversion of the host cell a-synuclein was accompanied by dramatic changes, including hyperphosphorylation and ubiquitination of a-synuclein aggregates—thus recapitulating some key features of the human pathology.
In experiments conceptually analogous to those discussed above, polyglutamine-containing protein aggregates similar to those present in Huntington’s disease and in spinocerebellar ataxias exhibited prion-like propagation (Ren et al., 2009). There, aggregation of huntingtin progressed from the extracellular space to the cytosol and eventually to the nucleus. What is more, similar phenomena occurred upon exposure of cells to Sup35 aggregates, which consist of a yeast protein for which there are no known mammalian paralogs. This suggests that the prionoid properties are intrinsic to amyloids and are not tied to the origin or function of their monomeric precursor protein.
In another work, Tolnay and colleagues report a similar phenomenon in a mouse model of ‘‘tauopathy,’’ a neurodegenerative disease due to intraneuronal aggregation of the microtubule- associated tau protein (Clavaguera et al., 2009). Aggregation- prone mutant tau, when extracted from the brain of transgenic mice, induced tauopathy in mice overexpressing wild-type tau. Assuming that tau pathology wasn’t elicited by some indirect pathway (tau-overexpressing mice develop tangles when exposed to Ab aggregates [Go¨ tz et al., 2001]), these transgenic mice appear to behave like the Martian bottles, since tauopathy was not induced in mice expressing normal levels of tau. In yet another study, the microtubule binding part of the full-length tau was found to attack and penetrate cells when added exogenously, and this again induced host tau misfolding (Frost et al., 2009). This study also showed that aggregated intracellular Tau spontaneously transferred between two cocultured cell populations (Frost et al., 2009). In the case of both tau and polyglutamines, the protein aggregates appear to gain access to the cytosol and to cause further aggregation of their host counterparts—presumably by nucleation.
The unifying characteristics of all these diseases is the aggregation of proteins into highly ordered stacks, termed amyloids irrespective of their size; the growth of these structures also exhibits generic features (Knowles et al., 2009) shared with a wide class of self-assembly phenomena characterized by elongation and fragmentation, such as the formation of analogous aggregates in micro-organisms and in vitro. Two conclusions can be drawn from the recent studies: (1) an unexpected number of amyloidogenic proteins can be released from affected cells in the form of extracellular amyloid seeds, and (2) even more surprisingly, these seeds can then re-enter other cells and nucleate the aggregation of their intracellular counterparts—in the cytosol or even in the nucleus. The biological and practical implications are far-reaching. On the one hand, cell therapies of aggregation diseases may be more difficult than anticipated, as the transplanted cells may undergo infection. A possible remedy could consist in the removal of the genes encoding the precursor of the offending proteins from the cells utilized for therapy—e.g., using the zinc-finger nuclease strategy (Hockemeyer et al., 2009). On the other hand, a novel paradigm of amyloid pathogenesis is emerging from these data, whereby each prionoid behaves as a self-assembling and self-replicating nanomachine.
Conversely, these findings raise a number of enigmas for which we are lacking any satisfactory answer. Whereas PrPC and the Ab are luminally exposed, a-synuclein and tau are cytoplasmic— and huntingtin is even nuclear. Aggregates of both Ab and PrPSc, as well as their monomeric precursors, are found in the extracellular space; it is hence intuitive that the nucleation process can propagate spatially across large distances. Instead, the propagation of cytoplasmic prionoids challenges our basic cell-biological understanding, since it posits that protein aggregates are released into the extracellular space and can subsequently reenter—and wreak havoc—in the cytosol of other cells. The release of cytosolic amyloids is supported by the amelioration of Lewy body pathology in a-synuclein transgenic mice immunized with human a-synuclein (Masliah et al., 2005). Similarly, anti-tau oligomer immunotherapy reduced brain pathology (Asuni et al., 2007), and immunization with mutant SOD1 led to clearance of SOD1 and delayed the onset of the disease in mice (Urushitani et al., 2007). All of these results indicate that cytosolic amyloids are somehow accessible to extracellular antibodies. This raises the question of how these proteins are released into the extracellular space (‘‘cytosol to lumen’’) and how they subsequently re-enter cellular cytosol (‘‘lumen to cytosol’’). Both events require trespassing lipid bilayer barriers—by no means a trivial feat for proteins, let alone highmolecular- weight aggregates.
snip...
Conclusion
The wave of these recent reports on the prion-like behavior of disparate pathogenic proteins raises many more questions than it answers. Here we have highlighted a number of open issues related to mechanisms of cell-to-cell spread of prionoids. The resolution of such issues may constitute the first step toward the development of rational strategies aimed at blocking transcellular propagation. There is justified hope that the latter may decelerate the progression of pathology and, consequently, help toward fighting the devastating outcome of aggregation proteinopathies.
http://www.cell.com/neuron/abstract/S0896-6273(09)01006-X
Sunday, July 18, 2010
Alzheimer's Assocition International Conference on Alzheimer's Disease (updated diagnostic criteria) 2010 July 10 - 15 Honolulu, Hawaii
http://betaamyloidcjd.blogspot.com/2010/07/alzheimers-assocition-international.html
Saturday, April 24, 2010
New connection between Alzheimer’s and prionic illnesses discovered
http://betaamyloidcjd.blogspot.com/2010/04/new-connection-between-alzheimers-and.html
Sunday, June 7, 2009
ALZHEIMER'S DISEASE IS TRANSMISSIBLE
http://betaamyloidcjd.blogspot.com/2009/06/alzheimers-disease-is-transmissible.html
Wednesday, April 14, 2010
Food Combination and Alzheimer Disease Risk A Protective Diet
http://betaamyloidcjd.blogspot.com/2010/04/food-combination-and-alzheimer-disease.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
Perspective
The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
Adriano Aguzzi1,* and Lawrence Rajendran2,* 1Institute of Neuropathology, University Hospital of Zu¨ rich, Schmelzbergstrasse 12, CH-8091 Zu¨ rich, Switzerland 2Systems and Cell Biology of Neurodegeneration, Psychiatry Research, University of Zurich, CH-8008 Zu¨ rich, Switzerland *Correspondence: adriano.aguzzi@usz.ch (A.A.), rajendran@bli.uzh.ch (L.R.) DOI 10.1016/j.neuron.2009.12.016
Recent reports indicate that a growing number of intracellular proteins are not only prone to pathological aggregation but can also be released and ‘‘infect’’ neighboring cells. Therefore, many complex diseases may obey a simple model of propagation where the penetration of seeds into hosts determines spatial spread and disease progression. We term these proteins prionoids, as they appear to infect their neighbors just like prions—but how can bulky protein aggregates be released from cells and how do they access other cells? The widespread existence of such prionoids raises unexpected issues that question our understanding of basic cell biology.
Imagine that you are a neuroscientist vacationing on Mars. One day you encounter a colony of Martians that, as it happens, look similar to water bottles. The Martians are highly distressed and seek your advice, as their community is plagued by an enigmatic transmissible disease. Intrigued, you agree to help. It turns out that the bodies of your exobiotic friends consist of bottles filled with a supersaturated salt solution. At some point crystals have started forming in one individual, and then crystallization has somehow been transferred to other community members. Lacking molecular insight, you would initially conclude that the Martians are affected by an infectious agent. Through ingenuity and technology, you may then discover that the infectious agent is exceedingly simple and homogeneous, that it lacks informational nucleic acids, and that it is generated both by ordered aggregation of an intrinsic precursor and by appositional growth of extrinsically added seeds. Your discovery will earn you the Intergalactic Nobel Prize, yet two crucial questions remain unanswered: how do the crystals transfer between individuals, and what can be done to prevent this from happening?
Middle-aged readers may feel reminded of the plot for Andromeda Strain, a stunningly prescient novel published in 1969 by the late Michael Crichton. But the sci-fi scenario described above is also the blueprint of Prusiner’s hypothesis of prion propagation. Over time, we have learned that prions consist of PrPSc, higher-order aggregates of a physiological protein termed PrPC. Accordingly, prions propagate through elongation and breakage of PrPSc aggregates (Aguzzi and Polymenidou, 2004)—not unlike the crystals vexing our extraterrestrial friends.
There is mounting evidence (Clavaguera et al., 2009; Frost et al., 2009; Ren et al., 2009; Desplats et al., 2009; Luk et al., 2009) suggesting that the events sketched above, far from being confined to science-fiction and prion diseases (whose incidence in humans is just z1/106/year), may underlie highly prevalent human diseases of the brain and many other organs. The unifying characteristics of all these diseases is the aggregation of proteins into highly ordered stacks, henceforth termed ‘‘amyloids’’ irrespective of their size. Since PrPSc undoubtedly fulfills the latter definition of amyloid, one is led to wonder whether the prion principle may be much more pervasive than previously appreciated and whether many more diseases of unknown cause may eventually turn out to rely on prion-like propagation (Table 1, upper panel). Even more intriguingly, a number of proteins appear to exert normal functions when arranged in highly ordered stacks that are similar to amyloids and to prionoids (Table 1, lower panel).
Prions and Prionoids
There is one crucial difference between bona fide prion diseases and all other amyloids and prion-like phenomena hitherto described in uni- and pluricellular organisms (Table 1). Prions are infectious agents, transmissible between individuals, and tractable with microbiological techniques—including, e.g., titer determinations. Even if certain amyloids of yeast and mammals appear to infect neighboring molecules and sometimes neighboring cells, they do not propagate within communities, and none of them were found to cause macroepidemics such as Kuru and bovine spongiform encephalopathy. We have therefore termed these self-aggregating proteins ‘‘prionoids’’ (Aguzzi, 2009), since the lack of microbiological transmissibility precludes their classification as true prions.
Some prionoids may soon qualify for an upgrade to prion status. At least in select settings, amyloid A (AA) amyloidosis may exist as a truly infectious disease based on a self-propagating protein. AA amyloid consists of orderly aggregated fragments of SAA protein, whose deposition can damage many organs of the body. Somewhat bizarrely, AA aggregation is also present in the liver of force-fed geese, hence contributing to the pathophysiology of foie gras (Solomon et al., 2007). AA seeds can induce amyloidosis upon transfer of white blood cells (Sponarova et al., 2008). Furthermore, AA seeds are excreted with the feces, and AA amyloidosis is endemic in populations of cheetah (Zhang et al., 2008). It is therefore tantalizing to suspect that amyloid may entertain the complete life cycle of an infectious agent, including transmission by the orofecal and hematogenous route—similarly to enteroviruses and, perhaps, scrapie prions. While there may be many other good reasons to avoid foie gras, including, e.g., animal welfare concerns, gourmets may not need to panic: under experimental conditions, AA amyloidosis is only transmitted to AgNO3-pretreated mice that display elevated levels of the SAA precursor protein.
Alzheimer’s disease (AD) has long been suspected to be a transmissible disease, but these suspicions have never materialized in epidemiological studies. On the other hand, Mathias Jucker and Lary Walker observed that injection of the Ab peptide from human AD brains induced robust and convincing aggregation of Ab in transgenic mice overexpressing the Ab precursor protein, APP (Kane et al., 2000; Meyer-Luehmann et al., 2006). Jucker’s finding raises an epistemologically significant question: if aggregation depends on the introduction of seeds and on the availability of the monomeric precursor, and if amyloid represents the primordial state of all proteins (Chiti and Dobson, 2006), wouldn’t all proteins—under appropriate conditions— give rise to prionoids in the presence of sufficient precursor?
The issues sketched above go well beyond AD and prions. There are many other diseases—not necessarily involving the nervous system—whose pathogenesis involves ordered aggregation of proteins, but for which there is no evidence of transmission between individuals. The best-studied of these are the systemic amyloidoses, which come about through the nucleation of some aggregation-prone proteins such as transthyretin and immunoglobulin light chains. Yet ordered protein aggregation is by no means confined to the ‘‘classical’’ amyloidoses and extends to a number of conditions, some of which have been rather unexpected.
Type II diabetes is yet another disease whose pathogenesis may involve ordered protein aggregation. Evidence to support this idea was discovered over a century ago (Opie, 1901) but was largely forgotten until recently. It is now evident that aggregation of islet amyloid polypeptide (IAPP) is an exceedingly frequent feature of type II diabetes. IAPP amyloids damage the insulin-producing b cells within pancreatic islets and may crucially contribute to the pathogenesis of diabetes (Hull et al., 2004). It is unknown, however, whether IAPP deposition simply accrues linearly with IAPP production or whether it spreads prion-like from one pancreatic islet to the next.
A body of recent work supports the idea that many aggregation proteinopathies are, in one way or another, transmissible. A recent report showed that a-synuclein is released from neurons and is then taken up by the neighboring cells, thereby aiding in a progressive spread of the protein (Desplats et al., 2009; Lee et al., 2005). When exogenously added to cultured cells, fluorescently labeled, recombinant a-synuclein was internalized from the extracellular milieu into the cytosol. Furthermore, injection of GFP-labeled mouse cortical neuronal stem cells into the hippocampus of a-synuclein-transgenic mice led to the efficient uptake of the host a-synuclein into the grafted cells after just 4 weeks. These findings are reminiscent of the observation that healthy fetal tissue, grafted into the brains of Parkinson’s disease patients, acquired intracellular Lewy bodies. The latter phenomenon is somewhat anecdotal and has been disputed (Mendez et al., 2008), yet it would be entirely compatible with the hypothesis that a-synuclein aggregates are prionoids (Li et al., 2008). A similar study conclusively demonstrated that exogenous a-synuclein fibrils induced the formation of Lewy body-like intracellular inclusions in vitro (Luk et al., 2009). This study also showed that the conversion of the host cell a-synuclein was accompanied by dramatic changes, including hyperphosphorylation and ubiquitination of a-synuclein aggregates—thus recapitulating some key features of the human pathology.
In experiments conceptually analogous to those discussed above, polyglutamine-containing protein aggregates similar to those present in Huntington’s disease and in spinocerebellar ataxias exhibited prion-like propagation (Ren et al., 2009). There, aggregation of huntingtin progressed from the extracellular space to the cytosol and eventually to the nucleus. What is more, similar phenomena occurred upon exposure of cells to Sup35 aggregates, which consist of a yeast protein for which there are no known mammalian paralogs. This suggests that the prionoid properties are intrinsic to amyloids and are not tied to the origin or function of their monomeric precursor protein.
In another work, Tolnay and colleagues report a similar phenomenon in a mouse model of ‘‘tauopathy,’’ a neurodegenerative disease due to intraneuronal aggregation of the microtubule- associated tau protein (Clavaguera et al., 2009). Aggregation- prone mutant tau, when extracted from the brain of transgenic mice, induced tauopathy in mice overexpressing wild-type tau. Assuming that tau pathology wasn’t elicited by some indirect pathway (tau-overexpressing mice develop tangles when exposed to Ab aggregates [Go¨ tz et al., 2001]), these transgenic mice appear to behave like the Martian bottles, since tauopathy was not induced in mice expressing normal levels of tau. In yet another study, the microtubule binding part of the full-length tau was found to attack and penetrate cells when added exogenously, and this again induced host tau misfolding (Frost et al., 2009). This study also showed that aggregated intracellular Tau spontaneously transferred between two cocultured cell populations (Frost et al., 2009). In the case of both tau and polyglutamines, the protein aggregates appear to gain access to the cytosol and to cause further aggregation of their host counterparts—presumably by nucleation.
The unifying characteristics of all these diseases is the aggregation of proteins into highly ordered stacks, termed amyloids irrespective of their size; the growth of these structures also exhibits generic features (Knowles et al., 2009) shared with a wide class of self-assembly phenomena characterized by elongation and fragmentation, such as the formation of analogous aggregates in micro-organisms and in vitro. Two conclusions can be drawn from the recent studies: (1) an unexpected number of amyloidogenic proteins can be released from affected cells in the form of extracellular amyloid seeds, and (2) even more surprisingly, these seeds can then re-enter other cells and nucleate the aggregation of their intracellular counterparts—in the cytosol or even in the nucleus. The biological and practical implications are far-reaching. On the one hand, cell therapies of aggregation diseases may be more difficult than anticipated, as the transplanted cells may undergo infection. A possible remedy could consist in the removal of the genes encoding the precursor of the offending proteins from the cells utilized for therapy—e.g., using the zinc-finger nuclease strategy (Hockemeyer et al., 2009). On the other hand, a novel paradigm of amyloid pathogenesis is emerging from these data, whereby each prionoid behaves as a self-assembling and self-replicating nanomachine.
Conversely, these findings raise a number of enigmas for which we are lacking any satisfactory answer. Whereas PrPC and the Ab are luminally exposed, a-synuclein and tau are cytoplasmic— and huntingtin is even nuclear. Aggregates of both Ab and PrPSc, as well as their monomeric precursors, are found in the extracellular space; it is hence intuitive that the nucleation process can propagate spatially across large distances. Instead, the propagation of cytoplasmic prionoids challenges our basic cell-biological understanding, since it posits that protein aggregates are released into the extracellular space and can subsequently reenter—and wreak havoc—in the cytosol of other cells. The release of cytosolic amyloids is supported by the amelioration of Lewy body pathology in a-synuclein transgenic mice immunized with human a-synuclein (Masliah et al., 2005). Similarly, anti-tau oligomer immunotherapy reduced brain pathology (Asuni et al., 2007), and immunization with mutant SOD1 led to clearance of SOD1 and delayed the onset of the disease in mice (Urushitani et al., 2007). All of these results indicate that cytosolic amyloids are somehow accessible to extracellular antibodies. This raises the question of how these proteins are released into the extracellular space (‘‘cytosol to lumen’’) and how they subsequently re-enter cellular cytosol (‘‘lumen to cytosol’’). Both events require trespassing lipid bilayer barriers—by no means a trivial feat for proteins, let alone highmolecular- weight aggregates.
snip...
Conclusion
The wave of these recent reports on the prion-like behavior of disparate pathogenic proteins raises many more questions than it answers. Here we have highlighted a number of open issues related to mechanisms of cell-to-cell spread of prionoids. The resolution of such issues may constitute the first step toward the development of rational strategies aimed at blocking transcellular propagation. There is justified hope that the latter may decelerate the progression of pathology and, consequently, help toward fighting the devastating outcome of aggregation proteinopathies.
http://www.cell.com/neuron/abstract/S0896-6273(09)01006-X
Sunday, July 18, 2010
Alzheimer's Assocition International Conference on Alzheimer's Disease (updated diagnostic criteria) 2010 July 10 - 15 Honolulu, Hawaii
http://betaamyloidcjd.blogspot.com/2010/07/alzheimers-assocition-international.html
Saturday, April 24, 2010
New connection between Alzheimer’s and prionic illnesses discovered
http://betaamyloidcjd.blogspot.com/2010/04/new-connection-between-alzheimers-and.html
Sunday, June 7, 2009
ALZHEIMER'S DISEASE IS TRANSMISSIBLE
http://betaamyloidcjd.blogspot.com/2009/06/alzheimers-disease-is-transmissible.html
Wednesday, April 14, 2010
Food Combination and Alzheimer Disease Risk A Protective Diet
http://betaamyloidcjd.blogspot.com/2010/04/food-combination-and-alzheimer-disease.html
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
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/
TSS
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