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

Transmission and spreading of tauopathy in transgenic mouse brain

Letter abstract

--------------------------------------------------------------------------------

Nature Cell Biology Published online: 7 June 2009 doi:10.1038/ncb1901

Transmission and spreading of tauopathy in transgenic mouse brain

Florence Clavaguera1, Tristan Bolmont2, R. Anthony Crowther3, Dorothee Abramowski4, Stephan Frank1, Alphonse Probst1, Graham Fraser3, Anna K. Stalder5, Martin Beibel4, Matthias Staufenbiel4, Mathias Jucker2, Michel Goedert3,6 & Markus Tolnay1,6

Top of pageHyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease1. In the disease process, neuronal tau inclusions first appear in the transentorhinal cortex from where they seem to spread to the hippocampal formation and neocortex2. Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular -amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. An abundance of tau inclusions, in the absence of -amyloid deposits, defines Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases1. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia3, 4, 5. Thus, transgenic mice expressing mutant (for example, P301S) human tau in nerve cells show the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein6, 8. By contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or show neurodegeneration7, 8. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces assembly of wild-type human tau into filaments and spreading of pathology from the site of injection to neighbouring brain regions.



Department of Neuropathology, Institute of Pathology, University of Basel, Basel, Switzerland. Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. MRC Laboratory of Molecular Biology, Cambridge, UK. Novartis Institutes for Biomedical Research, Basel, Switzerland. Neurology and Neurobiology, University Hospital, Basel, Switzerland. These authors contributed equally to this work Correspondence to: Michel Goedert3,6 e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000101/!x-usc:mailto:mtolnay@uhbs.ch

Correspondence to: Markus Tolnay1,6 e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000101/!x-usc:mailto:mg@mrc-lmb.cam.ac.uk



http://www.nature.com/ncb/journal/vaop/ncurrent/abs/ncb1901.html





CJD1/9 0185Ref: 1M51AIN STRICT CONFIDENCETRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES1.

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; andiii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.93/01.05/4.1



http://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




???



http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf




BSE101/1 0136IN CONFIDENCE5 NOV 1992CMO From: Dr J S Metters DCMO 4 November 1992TRANSMISSION 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.htmlre-




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




Sunday, June 7, 2009


ALZHEIMER'S DISEASE IS TRANSMISSIBLE



http://betaamyloidcjd.blogspot.com/2009/06/alzheimers-disease-is-transmissible.html

ALZHEIMER'S DISEASE IS TRANSMISSIBLE

Mice injected with Alzheimer's cast new light on dementia

Alok Jha guardian.co.uk, Sunday 7 June 2009 19.11 BST

Scientists have found that harmful tangles of proteins that cause diseases such as Alzheimer's can be transmitted from one brain to another, spreading and causing damage after being injected into the brains of mice. The researchers stressed, however, that Alzheimer's was not contagious and said it could not be caught, for example, through blood transfusions.

Alzheimer's and similar neurodegenerative diseases can be caused by the build-up in the brain of tangled masses of a type of protein called tau. They destroy brain function and, when they damage large amounts of tissue, can lead to dementia.

In experiments on mice, researchers found that the tau tangles could spread in the brain, as though they were an infectious agent, and be injected in tissue from the brain of an affected mouse into the brain of a healthy one. The research is published tomorrow in the journal Nature Cell Biology, and gives scientists a much better idea of how to target therapies for neurodegenerative diseases.

Michel Goedert of the Medical Research Council's Laboratory of Molecular Biology in Cambridge, who took part in the study, said the work opened up new avenues in understanding and allowing scientists to experiment with the causes of dementia.

"This research in mice does not show that tau pathology is contagious or it can spread easily from mouse to mouse - what it has revealed is how tau tangles spread within brain tissues of individual mice," he said. "It suggests that tangles of proteins that build up in the brain to cause symptoms could have some contagious properties within brain tissue but not between mice that haven't been injected with tissue from another mouse and certainly not between people." Though they are also bits of protein, tau tangles do transmit in the same way as prions, the proteins that cause diseases such as vCJD and mad cow disease by destroying brain tissue, because they cannot be passed easily between individuals.

Rebecca Wood, chief executive of the Alzheimer's Research Trust, said: "This greater understanding of how tangles spread in Alzheimer's may lead to new ways of stopping them and defeating the disease." Abnormal tangles build up in the brain during Alzheimer's and other diseases of the brain. It's not clear how that happens - but it is clear that Alzheimer's itself is not contagious. We desperately need more research like this to find answers to dementia, a cruel condition that affects 700,000 people in the UK."

There is still much unknown about the changes in tau protein that lead to tangle formation in humans and, eventually, widespread brain cell death. But

Susanne Sorensen, head of research at the Alzheimer's Society, said: "Each new piece of knowledge helps build a better picture and takes us closer to the point where we can stop loss of brain tissue and dementia for good."



http://www.guardian.co.uk/science/2009/jun/07/alzheimers-transmission-mice-dementia-research



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.

93/01.05/4.1



http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf



Regarding Alzheimer's disease

(note the substantial increase on a yearly basis)



http://collections.europarchive.org/tna/20080103032314/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://collections.europarchive.org/tna/20080102220341/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://collections.europarchive.org/tna/20080102223915/http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf




???



http://collections.europarchive.org/tna/20080102224230/http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf




BSE101/1 0136

IN CONFIDENCE

CMO

From: Dr J S Metters DCMO

4 November 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognised the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.

2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed", As the report emphasises the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible.

What are the implications for public health?

3. The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process, Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.

92/11.4/1.1

4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.

J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832

92/11.4/1.2


http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf



CJD1/9 0185

Ref: 1M51A

IN STRICT CONFIDENCE

From: Dr. A Wight

Date: 5 January 1993

Copies:

Dr Metters

Dr Skinner

Dr Pickles

Dr Morris

Mr Murray

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.

2. Briefly, the meeting agreed that:

i) Dr Ridley et als findings of experimental induction of B amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;

ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and

iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.

93/01.05/4.1


http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf



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



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



Wednesday, March 31, 2010

Neurobiology of Disease Molecular Cross Talk between Misfolded Proteins in Animal Models of Alzheimer's and Prion Diseases

http://betaamyloidcjd.blogspot.com/2010/03/neurobiology-of-disease-molecular-cross.html



Tuesday, August 26, 2008

Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3

http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html



P03.139

Cellular Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer's Amyloid Precursor Protein

Hooper, NM1; Parkin, ET1; Watt, NT1; Baybutt, H2; Manson, J2; Hussain, I3; Turner, AJ1 1University of Leeds, Institute of Molecular and Cellular Biology, UK; 2Roslin Institute, Neuropathogenesis Unit, UK; 3GlaxoSmithKline, Neurodegeneration Research, UK

Background: The normal cellular function of the prion protein (PrP), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD) in humans, remains enigmatic. Several studies have reported combinations of Alzheimer's Disease (AD) and CJD neuropathology and the Val/Met129 polymorphism in the PrP gene has been identified as a risk factor for early-onset AD, leading to speculation that there may be some pathogenic connection between these two neurodegenerative conditions. The amyloid ß (Aß) peptides that cause AD are derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by the ß-secretase (BACE1) and the g-secretase complex. Aim: As both APP and PrP are cleaved by zinc metalloproteases of the ADAM family, we investigated whether PrP alters the proteolytic processing of APP. Results: Here we show that expression of PrP in SH-SY5Y cells dramatically downregulated the cleavage of APP by BACE1 and reduced the secretion of Aß peptides into the conditioned medium by >92%. Conversely, siRNA reduction of endogenous PrP in N2a cells led to an increase in secreted Aß. Furthermore, levels of Aß were significantly increased in the brains of PrP null mice as compared with wild type mice. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases, did not inhibit the BACE1 cleavage of APP. To investigate whether the Val/Met129 polymorphism in human PrPC would alter the production of Aß, brains from mice with the human PrP gene with MM or VV 129 genotypes were analysed. In the MM mice there was a significant increase in Aß in the brains as compared with the VV mice. In the brains of two strains (79A and 87V) of scrapie-infected mice there was a significant increase in Aß peptides as compared to uninfected mice. Conclusions: Together these data reveal a novel function for PrP in regulating the processing of APP through inhibition of BACE1. The increase in APP processing in cells expressing disease-associated forms of PrP and in scrapie-infected brains raises the possibility that the increase in Aß may contribute to the neurodegeneration observed in prion diseases. Funded by the Medical Research Council of Great Britain.




P03.140

Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer's Amyloid Precursor Protein through Interaction with Glycosaminoglycans

Griffiths, HH; Parkin, ET; Watt, NT; Turner, AJ; Hooper, NM University of Leeds, Institute of Molecular and Cellular Biology, UK

Background: Proteolytic processing of the amyloid precursor protein (APP) by ßsecretase, BACE1, is the initial step in the production of the amyloid ß (Aß) peptide which is involved in the pathogenesis of Alzheimer's disease. We have shown that the cellular prion protein (PrP) inhibits the cleavage of APP by BACE1 in cell and animal models. Aim: To investigate the mechanism by which PrP inhibits the action of BACE1. Results: Neither PrPdeltaGPI, which is not membrane attached, nor PrP-CTM, which is anchored by a transmembrane domain and is excluded from cholesterol-rich lipid rafts, reduced cleavage of APP, suggesting that to inhibit the BACE1 cleavage of APP PrP has to be localised to lipid rafts. Coimmunoprecipitation experiments demonstrated that PrP physically interacts with BACE1. However, PrP did not alter the activity of BACE1 towards a fluorogenic peptide substrate nor perturb the dimerisation of BACE1. Using constructs of PrP lacking either the octapeptide repeats or the 4 residues KKRP at the N-terminus of the mature protein (PrPdeltaN), we demonstrate that the KKRP sequence but not the octapeptide repeats, is essential for regulating the BACE1 cleavage of APP. As the KKRP sequence is known to participate in glycosaminoglycan (GAG) binding, we confirmed that PrPdeltaN did not bind to immobilised heparin. Addition of heparin to SH-SY5Y cells increased the amount of APP cleaved by BACE1 in a concentration-dependent manner and reduced the amount of BACE1 coimmunoprecipitated with PrP, suggesting that GAGs are required for PrP to interact with BACE1 and inhibit APP processing. Of a range of GAGs, including dextran sulphate, hyaluronic acid and chondroitin sulphate, investigated there was complete correlation between those that could restore BACE1 cleavage of APP in PrP expressing cells and those that bound PrP. Conclusion: These data suggest a possible mechanism by which PrP regulates the ßcleavage of APP is through the N-terminus of PrP interacting via GAGs with one or more of the heparin binding sites on BACE1 within a subset of cholesterol-rich lipid rafts, thereby restricting access of BACE1 to APP. Funded by the Medical Research Council of Great Britain. P04.37 Comparison of the Neuropsychological Profile of Patients with Sporadic Creutzfeldt-Jakob Disease and Patients with Alzheimer's Krzovska, M1; Cepek, L1; Ratzka, P2; Döhlinger, S3; Uttner, I1; Wolf, Stefanie4; Irle, Eva4; Mollenhauer, Brit5; Kretzschmar, Hans A.6; Riepe, Matthias7; v. Arnim, Christine1; Otto, Markus1 1University of Ulm, Germany; 2Department of Neurology, Germany; 3University of Goettingen, Germany; 4University of Goettingen, Germany; 5Elena Klinik, Germany; 6LMU, Germany; 7University of Berlin, Germany Background:To evaluate the neuropsychological profile of sCJD we administered the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) in order to determine if and how the sCJD-Subgroups (Met/Met, Met/Val, Val/Val) have different results in the item analysis of the ADAS-cog. Furthermore, we studied how the scores differ from that of patients with Alzheimer's disease (AD). Methods:33 sCJD patients (11 with definite CJD and 22 with probable CJD) underwent neuropsychological testing with the ADAS-cog and Mini Mental State Exam (MMSE). Of these 31 were genotyped at the Codon 129 (11 Val/Val, 18 Met/Val and 2 Met/Met). The patients were matched in regards to sex and total ADAS-cog score with AD patients. The scores of the 11 ADAS-cog items were compared between the sCJD and the AD groups as well as between the sCJD-subgroups Met/Val and Val/Val and the AD group. Results:The ADAS-cog total score of the sCJD and AD groups was 22.6+/- 6.5, respectively. Regarding the single Item scores of the sCJD patient group and the AD patient group, there were statistically significant differences in the Items Constructional praxis, Word-finding difficulty in spontaneous speech and Spoken language ability. When comparing the sCJD subtypes with each other no statistically significant difference was found in the items. Conclusion: In the spee ain and constructional praxis there is indication of greater impairment in sCJD patients in general when compared with AD patients. A disturbance of the speech appears to be an important characteristic of the Met/Val and Val/Val subtypes of sCJD, and should therefore be the focus of special attention in future neuropsychological studies.


http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf



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



Article Posted: 04/15/2007 9:16:48 PM

Human and Animal Food Poisoning with Mad Cow a Slow Death

an editorial by Terry S. Singeltary Sr.

HUMAN AND ANIMAL FOOD POISONING WITH MAD COW DISEASEs A SLOW DEATH

WITH all the pet food deaths mounting from tainted pet food, all the suffering not only the animals are going through, but there owners as well, why are owners of these precious animals not crying about the mad cow tainted animal carcasses they poison there animals with everyday, and have been for decades, why not an uproar about that? well, let me tell you why, they don't drop dead immediately, it's a slow death, they simply call it FELINE and or CANINE ALZHEIMER'S DISEASE, DEMENTIA OR MAD CAT/DOG DISEASE i.e. FSE and they refuse to document CSE i.e.Canine Spongiform Encephalopathy, but it's there and there is some strange pathological findings on that topic that was convientantly swept under the rug. Sadly, this happens everyday with humans, once again confidently swept under the rug as Alzheimer's and or dementia i.e. fast Alzheimer's. Who wants to spend money on an autopsy on an old dog or cat? Sadly, it's the same with humans, you get old and demented your either die or your family puts you in an old folks home and forgets about you, then you die, and again, no autopsy in most cases. Imagine 4.5 annually with Alzheimer's, with and estimated 20+ million dieing a slow death by 2050, and in reality it will most likely be much higher than that now that the blood supply has been infiltrated with the TSE agent, and we now know that blood is another route and source for this hideous disease. It's hell getting old now a days.

NOW, for the ones that don't believe me, well mad cow has been in the USA for decades undetected officially, but the late Richard Marsh documented way back, again, swept under the rug. Then in 2003 in December, the first case of BSE was finally documented, by accident. Then you had the next two cases that were documented in Texas and Alabama, but it took an act of Congress, literally, to get those finally documented, and when they were finally documented, they were atypical BSE or Bovine Amyloid Spongiform Encephalopathy (BASE), which when transmitted to humans is not vCJD or nvCJD, but SPORADIC CJD. Now you might ask yourself what about that mad cow feed ban of August 4, 1997, the year my mother died from the Heidenhain Variant of Creutzfeldt Jakob Disease (confirmed), well that ruminant to ruminant was merely a regulation on paper that nobody enforced. Just last month there was 10+ PLUS MILLION POUNDS OF BANNED BLOOD TAINTED MBM DISPERSED INTO COMMERCE, and there is no way the FDA will ever recover it. It will be fed out again. 2006 was a banner year for FDA mad cow protein fed out into commerce. Looks like 2007 will be also. Our federal Government has failed us at every corner when it comes to food safety. maybe your dog, your cat, your mom, your dad, your aunt, or your uncle, but again, who cares, there old and demented, just put them down, or put them away. It's hell getting old. ...END

http://www.swnebr.net/newspaper/cgi-bin/articles/articlearchiver.pl?160273



Crushed heads (which inevitably involve brain and spinal cord material) are used to a limited extent but will also form one of the constituent raw materials of meat and bone meal, which is used extensively in pet food manufacturer...


http://collections.europarchive.org/tna/20080102163540/http://www.bseinquiry.gov.uk/files/yb/1989/03/17004001.pdf



don't think dogs can't get a TSE prion disease either ??? don't bet on it, it's already happened ;

CANINE SPONGIFORM ENCEPHALOPATHY


http://caninespongiformencephalopathy.blogspot.com/



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




http://betaamyloidcjd.blogspot.com/




TSS

'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration

Published online 25 February 2009 Nature doi:10.1038/news.2009.121

News

'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration.

Heidi Ledford

Prion proteins may react with amyloid-ß peptides inside the brain cells of Alzheimer's patients.Thomas Deerinck NCMIR/Science Photo LibraryNon-infectious prion proteins found in the brain may contribute to Alzheimer's disease, researchers have found.

The surprising new results, reported this week in Nature1, show that normal prion proteins produced naturally in the brain interact with the amyloid-ß peptides that are hallmarks of Alzheimer's disease. Blocking this interaction in preparations made from mouse brains halted some neurological defects caused by the accumulation of amyloid-ß peptide. It was previously thought that only infectious prion proteins, rather than their normal, non-infectious counterparts, played a role in brain degeneration.

The results have yet to be confirmed in humans, but suggest that targeting the non-infectious prion protein (PrPc) could provide an alternative route to treating Alzheimer's disease. "The need is huge," says Paul Aisen, an Alzheimer's researcher based at the neurosciences department of the University of California, San Diego. "And it's great news for the field when a new idea is brought forth with strong evidence that can lead to new therapeutic strategies."

Proteins misbehaving Alzheimer's disease has long been linked to the build-up of amyloid-ß peptides, first into relatively short chains known as oligomers, and then eventually into the long, sticky fibrils that form plaques in the brain. The oligomeric form of the peptide is thought to be toxic, but exactly how it acts in the brain is unknown.

Stephen Strittmatter and his colleagues at Yale University in New Haven, Connecticut searched for brain cell proteins that interact with amyloid-ß oligomers. To their surprise, they found PrPc, the normal, non-infectious prion protein.

Normal prion proteins are produced naturally in the brain, but can cause disease when they come into contact with an infectious form of the protein (PrPSc) that folds into an unusual conformation. These infectious prions convert innocuous prion proteins into the infectious form, which forms clumps and leads to neurodegenerative diseases, such as variant Creutzfeldt-Jakob disease, the human form of mad cow disease.

Strittmatter's team found that in brain slices taken from mice that were engineered to lack the prion protein, amyloid-ß did not cause defects in a process called long-term potentiation, which is important for long-term memory formation. Similarly, using an antibody to block the prion protein also prevented damage caused by the errant amyloid-ß peptides.

Therapeutic potential Researchers have struggled to determine what prion proteins normally do in the brain. Mice that lack the protein appear largely normal, with possible minor deficits in the generation of new neurons and responses to stress. A recent study found evidence that the prion protein may also be necessary for mice to have a normal sense of smell2.

Nevertheless, the results in mice suggest that blocking the protein may have unwanted side-effects, says Lennart Mucke, a neurologist at the Gladstone Institute of Neurological Disease in San Francisco, California. Although some are already at work to develop drugs that target the prion protein, these programmes target the infectious form of the protein and may not be useful in warding off Alzheimer's disease.

But Strittmatter and his colleagues mapped the region of the prion protein that interacts with amyloid-ß, giving researchers a clear target in the search for inhibitors of this interaction. Mucke, meanwhile, points out that an enzyme called a-secretase can cleave the prion protein at a site that would prevent it from binding to amyloid-ß. This same enzyme can also cleave amyloid-ß itself, meaning that enhancing that enzyme's activity could yield two strikes against Alzheimer's disease.

Although more work needs to be done to confirm the results in animal and human studies, Aisen says Alzheimer's disease researchers will welcome a new target in the fight against the frustrating disease. Clinical trials are underway to test drugs that aim to reduce the levels of amyloid-ß in the brain, but researchers are pessimistic about ever driving amyloid-ß levels down to zero. Meanwhile, treatments already on the market target symptoms of the disease, and not it's underlying cause.

"The treatments we have for Alzheimer's disease today are symptomatic and entirely inadequate," says Aisen. "There's no question that we need treatments that target the mechanisms behind neurodegeneration in Alzheimer's disease."

References Lauren, J. et al. Nature 457, 1128-1132 (2009). Le Pichon, C. E. et al. Nature Neuroscience 12, 60-69 (2008). Article PubMed ChemPort



http://www.nature.com/news/2009/090225/full/news.2009.121.html



Link found between Alzheimer's, mad cow protein Bernadette Tansey, Chronicle Staff Writer

Thursday, February 26, 2009

(02-25) 19:56 PST -- The latest in a recent flurry of clues on the workings of Alzheimer's disease comes from Yale University researchers who found a link between the disorder and the prion protein, which can cause mad cow disease and other maladies.

The Yale team found that the prion protein, whose normal function is to maintain brain health, may contribute to nerve damage if it becomes entangled with a protein fragment that scientists consider a chief suspect as a cause for Alzheimer's disease.

That suspect fragment, the amyloid beta peptide, builds up in the gluey plaques in the brain that are a characteristic sign of Alzheimer's, a progressive neurodegenerative disease. The amyloid peptide seems to stick to the prion protein, block its benign effects and interfere with learning and memory, the Yale group said in a paper published Wednesday in the journal Nature.

'Very tantalizing' "It's very tantalizing," said Dr. Lennart Mucke, director of the Gladstone Institute of Neurological Disease, who wrote a commentary on the Yale theory in the same issue. Mucke is part of a robust community of Bay Area scientists who are trying to ferret out the root causes of Alzheimer's disease and develop new medicines.

The prion work adds to a spate of new leads produced at the Gladstone Institute at UCSF's Mission Bay campus, the Buck Institute for Age Research in Novato, South San Francisco biotechnology leader Genentech Inc. and other research teams.

The study by Dr. Stephen Strittmatter and his Yale colleagues raises the possibility of a link between Alzheimer's and the family of prion diseases that includes mad cow disease and a related human neurodegenerative illness called Creutzfeldt-Jakob disease. But the evidence so far shows no sign that Alzheimer's disease involves a prion protein with the deformed structure seen in mad cow and Creutzfeldt-Jakob disease. Such misfolded prions can arise from genetic mutations or can be carried into the body by infectious particles from tainted meat.

Mucke said that the prion protein, if it is involved in Alzheimer's, is probably in its normal form. There's no evidence that the disease somehow releases infectious prions. "I don't believe it's communicable," he said.

Other new theories The prion study does not contradict other new theories about Alzheimer's, which all suggest fresh potential mechanisms by which the amyloid peptide or its parent, a protein called APP, may wreak destruction on the brain, said Dr. Dale Bredesen of the Buck Institute. Each theory opens potential new avenues to experimental therapies, he said. So far, much of the drug discovery in Alzheimer's has been focused on simply clearing the amyloid peptide and its plaques from the brain, on the theory that they cause broad physical or chemical damage, Bredesen said. But new work shows that APP and the amyloid peptide are involved in sensitive signaling networks that can go awry and destroy healthy nerves.

"I think we're seeing a fundamental switch in the view of the disease," he said. Recent failures of experimental drugs aimed at the amyloid peptide alone suggest that additional tactics are needed, he said. "Amyloid beta was the tip of the iceberg, but there's more."

Bredesen has his own overarching theory. He sees APP as a molecular switch on the nerves that flips between health and destruction. The protein can split up into three parts that each nourish the nerve. Or it can fracture differently into four parts that each attack the nerve - and one of those destructive four is the amyloid peptide, he said.

Search for a therapy In the search for a possible therapy for Alzheimer's, Bredesen is focusing on a molecule that seems to block the destruction switch. The nerve growth factor netrin-1 appears to curb the release of the amyloid peptide from APP, he said. Work is under way on methods to deliver netrin-1 to people with early signs of Alzheimer's, but it could take five years to produce an approved drug, he said.

Mucke said the Gladstone Institute is working on an array of strategies, which include preventing the amyloid peptide from finding molecules that pass along its destructive signals.

Scientists are starting to see Alzheimer's as a complex disease like cancer or hypertension, which can arise from various root causes. That means patients may need a cocktail of several drugs, and maybe a custom-made mix for each individual.

"I'm absolutely convinced that different people get Alzheimer's for different reasons, and drug development will have to take that into account," Mucke said.

E-mail Bernadette Tansey at mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000117/!x-usc:mailto:btansey@sfchronicle.com.



http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2009/02/25/MNC7164VHL.DTL




> Mucke said that the prion protein, if it is involved in Alzheimer's, is probably in its normal form. There's no evidence

> that the disease somehow releases infectious prions. "I don't believe it's communicable," he said.


Greetings,


LOT of if's, probably's, and don't believe's still. BUT let's take a closer look at the old science i.e. transmission studies ;


IN STRICT CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES



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



Human BSE

snip...

These are not relevant to any possible human hazard from BSE nor to the much more common dementia, Alzheimers.

snip...



http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf




CJD1/9 0185

Ref: 1M51A

IN STRICT CONFIDENCE

Dr McGovern From: Dr A Wight

Date: 5 January 1993

Copies: Dr Metters

Dr Skinner

Dr Pickles

Dr Morris

Mr Murray

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.

2. Briefly, the meeting agreed that:

i) Dr Ridley et als findings of experimental induction of 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



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

1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognised the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.

2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasises the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning funher research to sec if the conditions, as opposed to the partial pathological process, is transmissible.

What are the implications for public health?

3. . The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.

92/11.4/1-1

BSE101/1 0137

4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed m GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.

JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832

121/YdeStss

92/11.4/1.2



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



IN STRICT CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES



http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.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




P03.139 Cellular Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein

Hooper, NM1; Parkin, ET1; Watt, NT1; Baybutt, H2; Manson, J2; Hussain, I3; Turner, AJ1 1University of Leeds, Institute of Molecular and Cellular Biology, UK; 2Roslin Institute, Neuropathogenesis Unit, UK; 3GlaxoSmithKline, Neurodegeneration Research, UK

Background: The normal cellular function of the prion protein (PrP), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD) in humans, remains enigmatic. Several studies have reported combinations of Alzheimer’s Disease (AD) and CJD neuropathology and the Val/Met129 polymorphism in the PrP gene has been identified as a risk factor for early-onset AD, leading to speculation that there may be some pathogenic connection between these two neurodegenerative conditions. The amyloid ß (Aß) peptides that cause AD are derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by the ß-secretase (BACE1) and the g-secretase complex. Aim: As both APP and PrP are cleaved by zinc metalloproteases of the ADAM family, we investigated whether PrP alters the proteolytic processing of APP. Results: Here we show that expression of PrP in SH-SY5Y cells dramatically downregulated the cleavage of APP by BACE1 and reduced the secretion of Aß peptides into the conditioned medium by >92%. Conversely, siRNA reduction of endogenous PrP in N2a cells led to an increase in secreted Aß. Furthermore, levels of Aß were significantly increased in the brains of PrP null mice as compared with wild type mice. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases, did not inhibit the BACE1 cleavage of APP. To investigate whether the Val/Met129 polymorphism in human PrPC would alter the production of Aß, brains from mice with the human PrP gene with MM or VV 129 genotypes were analysed. In the MM mice there was a significant increase in Aß in the brains as compared with the VV mice. In the brains of two strains (79A and 87V) of scrapie-infected mice there was a significant increase in Aß peptides as compared to uninfected mice. Conclusions: Together these data reveal a novel function for PrP in regulating the processing of APP through inhibition of BACE1. The increase in APP processing in cells expressing disease-associated forms of PrP and in scrapie-infected brains raises the possibility that the increase in Aß may contribute to the neurodegeneration observed in prion diseases. Funded by the Medical Research Council of Great Britain.

P03.140 Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein through Interaction with Glycosaminoglycans

Griffiths, HH; Parkin, ET; Watt, NT; Turner, AJ; Hooper, NM University of Leeds, Institute of Molecular and Cellular Biology, UK

Background: Proteolytic processing of the amyloid precursor protein (APP) by ßsecretase, BACE1, is the initial step in the production of the amyloid ß (Aß) peptide which is involved in the pathogenesis of Alzheimer’s disease. We have shown that the cellular prion protein (PrP) inhibits the cleavage of APP by BACE1 in cell and animal models. Aim: To investigate the mechanism by which PrP inhibits the action of BACE1. Results: Neither PrPdeltaGPI, which is not membrane attached, nor PrP-CTM, which is anchored by a transmembrane domain and is excluded from cholesterol-rich lipid rafts, reduced cleavage of APP, suggesting that to inhibit the BACE1 cleavage of APP PrP has to be localised to lipid rafts. Coimmunoprecipitation experiments demonstrated that PrP physically interacts with BACE1. However, PrP did not alter the activity of BACE1 towards a fluorogenic peptide substrate nor perturb the dimerisation of BACE1. Using constructs of PrP lacking either the octapeptide repeats or the 4 residues KKRP at the N-terminus of the mature protein (PrPdeltaN), we demonstrate that the KKRP sequence but not the octapeptide repeats, is essential for regulating the BACE1 cleavage of APP. As the KKRP sequence is known to participate in glycosaminoglycan (GAG) binding, we confirmed that PrPdeltaN did not bind to immobilised heparin. Addition of heparin to SH-SY5Y cells increased the amount of APP cleaved by BACE1 in a concentration-dependent manner and reduced the amount of BACE1 coimmunoprecipitated with PrP, suggesting that GAGs are required for PrP to interact with BACE1 and inhibit APP processing. Of a range of GAGs, including dextran sulphate, hyaluronic acid and chondroitin sulphate, investigated there was complete correlation between those that could restore BACE1 cleavage of APP in PrP expressing cells and those that bound PrP. Conclusion: These data suggest a possible mechanism by which PrP regulates the ßcleavage of APP is through the N-terminus of PrP interacting via GAGs with one or more of the heparin binding sites on BACE1 within a subset of cholesterol-rich lipid rafts, thereby restricting access of BACE1 to APP. Funded by the Medical Research Council of Great Britain. P04.37 Comparison of the Neuropsychological Profile of Patients with Sporadic Creutzfeldt-Jakob Disease and Patients with Alzheimer’s Krzovska, M1; Cepek, L1; Ratzka, P2; Döhlinger, S3; Uttner, I1; Wolf, Stefanie4; Irle, Eva4; Mollenhauer, Brit5; Kretzschmar, Hans A.6; Riepe, Matthias7; v. Arnim, Christine1; Otto, Markus1 1University of Ulm, Germany; 2Department of Neurology, Germany; 3University of Goettingen, Germany; 4University of Goettingen, Germany; 5Elena Klinik, Germany; 6LMU, Germany; 7University of Berlin, Germany Background:To evaluate the neuropsychological profile of sCJD we administered the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) in order to determine if and how the sCJD-Subgroups (Met/Met, Met/Val, Val/Val) have different results in the item analysis of the ADAS-cog. Furthermore, we studied how the scores differ from that of patients with Alzheimer’s disease (AD). Methods:33 sCJD patients (11 with definite CJD and 22 with probable CJD) underwent neuropsychological testing with the ADAS-cog and Mini Mental State Exam (MMSE). Of these 31 were genotyped at the Codon 129 (11 Val/Val, 18 Met/Val and 2 Met/Met). The patients were matched in regards to sex and total ADAS-cog score with AD patients. The scores of the 11 ADAS-cog items were compared between the sCJD and the AD groups as well as between the sCJD-subgroups Met/Val and Val/Val and the AD group. Results:The ADAS-cog total score of the sCJD and AD groups was 22.6+/- 6.5, respectively. Regarding the single Item scores of the sCJD patient group and the AD patient group, there were statistically significant differences in the Items Constructional praxis, Word-finding difficulty in spontaneous speech and Spoken language ability. When comparing the sCJD subtypes with each other no statistically significant difference was found in the items. Conclusion: In the spee h domain and constructional praxis there is indication of greater impairment in sCJD patients in general when compared with AD patients. A disturbance of the speech appears to be an important characteristic of the Met/Val and Val/Val subtypes of sCJD, and should therefore be the focus of special attention in future neuropsychological studies.


http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf



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




From: TSS Subject: CJD or Alzheimer's, THE PA STUDY...full text Date: May 7, 2001 at 10:24 am PST

Diagnosis of dementia: Clinicopathologic correlations

Francois Boller, MD, PhD; Oscar L. Lopez, MD; and John Moossy, MD

Article abstract--Based on 54 demented patients consecutively autopsied at the University of Pittsburgh, we studied the accuracy of clinicians in predicting the pathologic diagnosis. Thirty-nine patients (72.2%) had Alzheimer's disease, while 15 (27.7%) had other CNS diseases (four multi-infarct dementia; three Creutzfeldt-Jakob disease; two thalamic and subcortical gliosis; three Parkinson's disease; one progressive supranuclear palsy; one Huntington's disease; and one unclassified). Two neurologists independently reviewed the clinical records of each patient without knowledge of the patient's identity or clinical or pathologic diagnoses; each clinician reached a clinical diagnosis based on criteria derived from those of the NINCDS/ADRDA. In 34 (63 %) cases both clinicians were correct, in nine (17%) one was correct, and in 11 (20%) neither was correct. These results show that in patients with a clinical diagnosis of dementia, the etiology cannot be accurately predicted during life.

NEUROLOGY 1989;39:76-79

Address correspondence and reprint requests to Dr. Boller, Department of Neurology, 322 Scaife Hall, University of Pittsburgh Medical School, Pittsburgh, PA 15261.

January 1989 NEUROLOGY 39 79

snip...

From: TSS (216-119-130-151.ipset10.wt.net) Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia Date: May 8, 2001 at 6:27 pm PST

Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia Date: Tue, 8 May 2001 21:09:43 -0700 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000117/!x-usc:mailto:BSE-L@uni-karlsruhe.de

#### Bovine Spongiform Encephalopathy ####

Evaluation of Cerebral Biopsies for the Diagnosis of Dementia

Christine M. Hulette, MD; Nancy L. Earl, Md; Barbara J. Crain, MD, Phd

To identify those patients most likely to benefit from a cerebral biopsy to diagnose dementia, we reviewed a series of 14 unselected biopsies performed during a 9-year period (1980 through 1989) at Duke University Medical Center, Durham, NC. Pathognomonic features allowed a definitive diagnosis in seven specimens. Nondiagnostic abnormalities but not diagnostic neuropathologic changes were seen in five additional specimens, and two specimens were normal. Creutzfeldt-Jakob disease was the most frequent diagnosis. One patient each was diagnosed as having Alzheimer's disease, diffuse Lewy body disease, adult-onset Niemann-Pick disease, and anaplastic astrocytoma. We conclude that a substantial proportion of patients presenting clinically with atypical dementia are likely to receive a definitive diagnosis from a cerebral biopsy. However, in those with coexisting hemiparesis, chorea, athetosis, or lower motor neuron signs, cerebral biopsies are less likely to be diagnostic. (Arch Neurol. 1992;49:28-31)

"Dementia" is a syndrome characterized by global deterioration of cognitive abilities and is the general term used to describe the symptom complex of intellectual deterioration in the adult. It is associated with multiple causes, although Alzheimer's disease (AD) alone accounts for approximately 60% of cases.1-3...

snip...

Subject: Re: Hello Dr. Manuelidis
Date: Fri, 22 Dec 2000 17:47:09 -0500
From: laura manuelidis
Reply-To: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000117/!x-usc:mailto:laura.manuelidis@yale.edu Organization: Yale Medical School
To: "Terry S. Singeltary Sr."


References: <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000117/!x-usc:mailto:39B5561A.87B84A28@wt.net> <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000117/!x-usc:mailto:39B64574.A4835745@yale.edu> <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000117/!x-usc:mailto:39B680D8.3872535B@wt.net> <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000117/!x-usc:mailto:39B66EF1.4CE25685@yale.edu> <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000117/!x-usc:mailto:39BBB812.425109F@wt.net> <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000117/!x-usc:mailto:39BE84CB.D7C0C16B@yale.edu> <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000117/!x-usc:mailto:3A3BA197.7F60D376@wt.net>


Dear Terry,

One of our papers (in Alzheimer's Disease Related Disord. 3:100-109, 1989) in text cites 6 of 46 (13%) of clinical AD as CJD. There may be a later paper from another lab showing the same higher than expected incidence but I can't put my hands on it right now. We also have a lot of papers from 1985 on stating that there are likely many silent (non-clinical) CJD infections, i.e. much greater than the "tip of the iceberg" of long standing end-stage cases with clinical symptoms. Hope this helps.

best wishes for the new year laura manuelidis

end...TSS


=============================



Subject: Alzheimer's, CJD, TSE, and the AA amyloidosis
From: "Terry S. Singeltary Sr." <[log in to unmask]>
Reply-To: Sustainable Agriculture Network Discussion Group <[log in to unmask]>
Date: Sun, 24 Jun 2007 18:10:49 -0500 Content-Type: text/plain Parts/Attachments: text/plain (515 lines)

Subject: Amyloidogenic potential of foie gras Date: June 22, 2007 at 2:23 pm PST

Amyloidogenic potential of foie gras

Alan Solomon*†, Tina Richey*, Charles L. Murphy*, Deborah T. Weiss*, Jonathan S. Wall*, Gunilla T. Westermark‡, and Per Westermark§ *Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920; ‡Division of Cell Biology, Linko¨ ping University, SE-58185 Linko¨ ping, Sweden; and §Department of Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden Communicated by D. Carleton Gajdusek, Institut de Neurobiologie Alfred Fessard, Gif-sur-Yvette, France, January 30, 2007 (received for review October 10, 2006)

The human cerebral and systemic amyloidoses and prionassociated spongiform encephalopathies are acquired or inherited protein folding disorders in which normally soluble proteins or peptides are converted into fibrillar aggregates. This is a nucleation-dependent process that can be initiated or accelerated by fibril seeds formed from homologous or heterologous amyloidogenic precursors that serve as an amyloid enhancing factor (AEF) and has pathogenic significance in that disease may be transmitted by oral ingestion or parenteral administration of these conformationally altered components. Except for infected brain tissue, specific dietary sources of AEF have not been identified. Here we report that commercially available duck- or goose-derived foie gras contains birefringent congophilic fibrillar material composed of serum amyloid A-related protein that acted as a potent AEF in a transgenic murine model of secondary (amyloid A protein) amyloidosis. When such mice were injected with or fed amyloid extracted from foie gras, the animals developed extensive systemic pathological deposits. These experimental data provide evidence that an amyloid-containing food product hastened the development of amyloid protein A amyloidosis in a susceptible population. On this basis, we posit that this and perhaps other forms of amyloidosis may be transmissible, akin to the infectious nature of prion-related illnesses. amyloid protein A amyloidosis
amyloid-enhancing factor
protein aggregation
rheumatoid arthritis
transmissibility Amyloid protein A amyloidosis (AA) occurs in patients with rheumatoid arthritis and other chronic inflammatory diseases and results from a sustained elevation of the apolipoprotein serum amyloid A (SAA) protein produced by hepatocytes under regulation by interleukin (IL)-1, IL-6, and tumor necrosis factor (1). This acute-phase reactant is cleaved into an
76- residue N-terminal fragment deposited as amyloid predominately in the kidneys, liver, and spleen. The disorder also can be induced experimentally in susceptible strains of mice by inflammatory stimuli that result in an 1,000-fold increase in SAA concentration (2). Further, the lag phase of this process is greatly decreased by injecting or feeding animals extracts of amyloidladen spleens of affected mice (2–5). To determine whether amyloid-containing food products exhibit amyloid enhancing factor (AEF) activity, we used a more robust in vivo murine model of AA amyloidosis involving mice carrying the human IL-6 (hIL-6) gene under control of either the murine metallothionein-1 (MT-1) (MT-1/hIL-6) or histocompatibility H2-Ld (H2/hIL-6) promoter (6). Typically, AA amyloid develops in these animals at
5 mo of age and is initially located predominately in the perifollicular regions of the spleen. Over the next 2–3 mo, the deposits spread rapidly into the liver parenchyma, renal glomerular and intertubular regions, cardiac muscle, tongue, and gastrointestinal tract and lead to death at
8–9 mo. However, by injection into 8-wk-old transgenic mice of a single 100-
g i.v. dose of an exogenous source of AA fibrils, amyloid deposits are formed within 3 wk, and severe systemic disease (akin to that found in 8-mo-old animals) occurs within 2 mo, at which time the resultant pathology is lethal (7). AA amyloid deposits are commonly found in waterfowl, particularly Pekin ducks, in which the liver is predominately involved (8–10). This pathologica alteration is noticeably increased in birds subjected to stressful environmental conditions as well as to the forced feeding that is used to produce foie gras (8). This culinary product, derived from massively enlarged fatty livers results from gorging young ducks or geese up to three times daily over a 4-wk period with corn-based feed. We now report the results of our studies that have shown that AA-containing fibrils extracted from duck or goose foie gras have potent AEF activity when administered by i.v. injection or gavage into our IL-6 transgenic mice. Results and Discussion We analyzed several commercial sources of foie gras histochemically and found amyloid to be present. Microscopic examination of hematoxylin/eosin- and Congo red-stained sections cut from formalin-fixed, paraffin-embedded specimens revealed virtual replacement of the normal hepatic parenchyma by fat; additionally, green birefringent congophilic areas in residual vasculature were noted by polarizing microscopy (Fig. 1 a and b). Further, these deposits were immunostained by a specific anti-AA antiserum (Fig. 1c). Similar material was found in marketed paˆte´s prepared from duck or goose liver (Fig. 2). The AA composition of the hepatic amyloid deposits was confirmed chemically through analysis of material derived from acetone-defatted specimens extracted first with 0.15MNaCl and then distilled water. The isolates were strongly congophilic, and, when examined by transmission electron microscopy, contained fibrils with the typical ultrastructural features of amyloid; namely,
10-
m-thick unbranched structures (Fig. 3a). Electrophoresis of the water-suspended product on a SDS/ polyacrylamide gel in the presence of 0.1 M DTT and 8 M urea revealed, after Coomassie blue staining, a protein band with aMr of 6,000, comparable to that of amyloid extracted from the spleen of a mouse with AA amyloidosis (Fig. 3b). After transfer to a PVDF membrane, this component was subjected to automated Edman degradation with which 14 residues identical in amino acid sequence to that of the N-terminal portion of duck SAA were detected. In a similar study of tryptic digests obtained from cleavage of this molecule after reduction and alkylation, six peptides that included 45 of the first 60 residues of duck SAA were identified by MS/MS (Fig. 3c) (9).

Author contributions: A.S., J.S.W., and P.W. designed research; T.R. and C.L.M. performed research; J.S.W., G.T.W., and P.W. analyzed data; A.S. and D.T.W. wrote the paper. The authors declare no conflict of interest. Freely available online through the PNAS open access option. Abbreviations: AA, amyloid protein A amyloidosis; AEF, amyloid enhancing factor; IL, interleukin; SAA, serum amyloid A protein. †To whom correspondence should be addressed at: University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37920. E-mail: asolomon@ mc.utmck.edu. This article contains supporting information online at www.pnas.org/cgi/content/full/ 0700848104/DC1. © 2007 by The National Academy of Sciences of the USA 10998–11001
PNAS
June 26, 2007
vol. 104
no. 26


www.pnas.orgcgidoi10.1073pnas.0700848104



Subject: Re: Amyloidogenic potential of foie gras Date: June 22, 2007 at 2:26 pm PST

Vet Pathol 40:71–80 (2003) Pathology of AA Amyloidosis in Domestic Sheep and Goats C. ME´ NSUA, L. CARRASCO, M. J. BAUTISTA, E. BIESCAS, A. FERNA´ NDEZ, C. L. MURPHY, D. T. WEISS, A. SOLOMON, AND L. LUJA´ N Department of Animal Pathology, University of Zaragoza, Veterinary Faculty, Zaragoza, Spain (CM, EB, AF, LL); Department of Anatomy and Comparative Pathology, University of Co´rdoba, Veterinary Faculty, Campus de Rabanales, Co´rdoba, Spain (LC, MJB); and Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, TN (CLM, DTW, AS) Abstract. We describe the main pathologic changes in small ruminants affected by AA amyloidosis, together with the partial sequence of the protein involved. Twenty-one sheep and one goat were selected for presenting macroscopic kidney lesions compatible with systemic amyloidosis. Available tissue samples were studied by histologic, immunopathologic, and ultrastructural means. Renal lesions were characterized grossly by pale cortical surfaces with scattered, miliary, whitish-yellow foci and on cut cortical surfaces by straight, whitish-yellow striations. Gangrenous pneumonia was observed in 16 out of 21 affected sheep (76.2%), although other chronic inflammations were also observed. Amyloid was detected in all grossly affected kidneys using Congo red staining, lesions being most remarkable in glomeruli, affecting 95.5% of animals studied. Congophilic deposits were also observed in intertubular interstitium (68.2%) and medulla (57.1%). All amyloid-affected animals presented proximal convoluted tubule lesions, mostly characterized by an increase in diameter and by hyaline granular degeneration that were responsible for the macroscopic appearance of the kidney. Histologically, amyloid was also seen in blood vessels, spleen, liver, lymph nodes, gastrointestinal tract, and adrenal glands. All amyloid deposits demonstrated greenish-yellow birefringence with polarized light, and the antisera prepared against goat amyloid extracts specifically reacted with birefringent congophilic deposits of both sheep and goats. Ultrastructurally, these deposits were formed by masses of straight, nonbranching fibrils located predominantly in the basement membranes of glomerular capillaries and in the mesangium. Partial sequence of the protein in sheep and goats indicated a high degree of homology with the previously reported sequence of sheep Serum Amyloid A. Key words: AA amyloidosis, amyloid, goats, kidney, sheep, small ruminants.

===========================================

Subject: Inactivation of amyloid-enhancing factor (AEF): study on experimental murine AA amyloidosis Date: June 24, 2007 at 1:11 pm PST

Masatoshi Omoto · Tadaaki Yokota · Dan Cui Yoshinobu Hoshii · Hiroo Kawano · Toshikazu Gondo Tokuhiro Ishihara · Takashi Kanda

Inactivation of amyloid-enhancing factor (AEF): study on experimental murine AA amyloidosis

Abstract It is known that amyloid-enhancing factor (AEF) shortens the preamyloid phase in experimentally induced AA amyloidosis in mice. Because it is reported that AEF serves as both a nidus and a template for amyloid formation, AA amyloidosis may have transmissibility by a prionlike mechanism. It has been shown that amyloid fi brils also have AEF activity, and amyloid fi brils with AEF activity were named fi bril-amyloid enhancing factor (F-AEF). In this study, we investigated methods to inactivate the AEF activity. AEF was extracted from the thyroid gland obtained at autopsy of a patient with AA amyloidosis. Before injection into mice, AEF was treated with several methods for inactivation. Of all the tested treatments, 1 N NaOH, 0.1 N NaOH, and autoclaving consistently demonstrated complete inactivation of AEF. Heat treatment led to incomplete inactivation, but 0.01 N NaOH, 0.001 N NaOH, pepsin, trypsin, pronase, and proteinase K treatment had no effect on AEF activity. By analysis with transmission electron microscopy, the AEF preparation contains amyloid fi brils, and a change of ultrastructure was shown after 1 N NaOH, 0.1 N NaOH, and autoclaving treatment. Furthermore, immunoblotting of AEF with antihuman AA antibody revealed that the protein band was scarcely found after autoclaving, 1 N NaOH, and 0.1 N NaOH treatment. Our results suggest that, similar to Creutzfeldt–Jakob M. Omoto (*) · T. Kanda Department of Neurology and Clinical Neuroscience, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube City, Yamaguchi 755-8505, Japan Tel. +81-836-22-2719; Fax +81-836-22-2364 e-mail: [log in to unmask] T. Yokota Department of Pathology, Kokura Memorial Hospital, Yamaguchi, Japan D. Cui · Y. Hoshii · H. Kawano · T. Ishihara Department of Radiopathological and Science, Yamaguchi University School of Medicine, Fukuoka, Japan T. Gondo Department of Surgical Pathology, Yamaguchi University Hospital, Yamaguchi, Japan disease (CJD), amyloidosis may require chemical or autoclaving decontamination. Key words Amyloid-enhancing factor · Amyloidosis · Creutzfeldt–Jakob disease · Prion · Transmission electron

============================================

In our experiments with mice, the activity of F-AEF was markedly decreased after autoclaving treatment under conditions of 132°C for 1 h and 1 N NaOH and 0.1 N NaOH treatment for 1 h. For CJD materials, the Committee on Health Care Issues of the American Neurological Association recommended treatment with 1 N NaOH as a standard sterilization procedure.18 Heat treatment led to substantial but incomplete inactivation in this study. The Committee on Health Care Issues of the American Neurological Association reported that boiling was an ineffective procedure for CJD tissues and contaminated materials.18 Tateishi et al. showed that heat treatment with SDS was effective.17 The acceleration of amyloid deposition may be a primary event in disease, CJD, bovine spongiform encephalopathy (BSE), familial amyloid polyneuropathy, and AA and human senile systemic amyloidosis.32 Walker et al. reported Aß amyloid extracted from an Alzheimer disease brain may have potential of prion protein.33

The property described for F-AEF is similar to that of prion reported in CJD. Chemical or autoclaving decontamination for CJD is necessary for most items associated with surgery or autopsy.34 We suggest that amyloidosis may need chemical or autoclaving decontamination similar to CJD.

Acknowledgments We thank Mr. Jitsuo Kashitani for excellent technical assistance. This work was supported by a grant from the Intractable Disease Division, the Ministry of Health and Welfare, a Research Committee for Epochal Diagnosis and Treatment of amyloidosis in Japan, and a Research Committee for amyloidosis.



http://www.springerlink.com/content/j6257362375470q8/fulltext.pdf



Alzheimer-type neuropathology 28 year old patient with idCJD Sun Feb 19, 2006 11:14 71.248.144.164

SHORT REPORT Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting M Preusser1, T Ströbel1, E Gelpi1,2, M Eiler3, G Broessner4, E Schmutzhard4 and H Budka1,2 1 Institute of Neurology, Medical University Vienna, Austria 2 Austrian Reference Centre for Human Prion Diseases (OERPE), General Hospital Vienna, Austria 3 Department of Neurology, LKH Rankweil, Austria 4 Department of Neurology, Medical University Innsbruck, Innsbruck, Austria

Correspondence to: Dr H Budka Institute of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 4J, 1097 Vienna, Austria; [log in to unmask]

ABSTRACT We report the case of a 28 year old man who had received a cadaverous dura mater graft after a traumatic open skull fracture with tearing of the dura at the age of 5 years. A clinical suspicion of Creutzfeldt-Jakob disease (CJD) was confirmed by a brain biopsy 5 months prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according to WHO criteria. Immunohistochemistry showed widespread cortical depositions of disease associated prion protein (PrPsc) in a synaptic pattern, and western blot analysis identified PrPsc of type 2A according to Parchi et al. Surprisingly, we found Alzheimer-type senile plaques and cerebral amyloid angiopathy in widespread areas of the brain. Plaque-type and vascular amyloid was immunohistochemically identified as deposits of beta-A4 peptide. CERAD criteria for diagnosis of definite Alzheimer’s disease (AD) were met in the absence of neurofibrillar tangles or alpha-synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any other neurological disease, and genetic analysis showed no disease specific mutations of the prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents (a) the iCJD case with the longest incubation time after dural grafting reported so far, (b) the youngest documented patient with concomitant CJD and Alzheimer-type neuropathology to date, (c) the first description of Alzheimer-type changes in iCJD, and (d) the second case of iCJD in Austria. Despite the young patient age, the Alzheimer-type changes may be an incidental finding, possibly related to the childhood trauma.

----------------------------------------------------------------------------




http://jnnp.bmjjournals.com/





Article Posted: 04/15/2007 9:16:48 PM

Human and Animal Food Poisoning with Mad Cow a Slow Death

an editorial by Terry S. Singeltary Sr.

HUMAN AND ANIMAL FOOD POISONING WITH MAD COW DISEASEs A SLOW DEATH

WITH all the pet food deaths mounting from tainted pet food, all the suffering not only the animals are going through, but there owners as well, why are owners of these precious animals not crying about the mad cow tainted animal carcasses they poison there animals with everyday, and have been for decades, why not an uproar about that? well, let me tell you why, they don't drop dead immediately, it's a slow death, they simply call it FELINE and or CANINE ALZHEIMER'S DISEASE, DEMENTIA OR MAD CAT/DOG DISEASE i.e. FSE and they refuse to document CSE i.e.Canine Spongiform Encephalopathy, but it's there and there is some strange pathological findings on that topic that was convientantly swept under the rug. Sadly, this happens everyday with humans, once again confidently swept under the rug as Alzheimer's and or dementia i.e. fast Alzheimer's. Who wants to spend money on an autopsy on an old dog or cat? Sadly, it's the same with humans, you get old and demented your either die or your family puts you in an old folks home and forgets about you, then you die, and again, no autopsy in most cases. Imagine 4.5 annually with Alzheimer's, with and estimated 20+ million dieing a slow death by 2050, and in reality it will most likely be much higher than that now that the blood supply has been infiltrated with the TSE agent, and we now know that blood is another route and source for this hideous disease. It's hell getting old now a days.

NOW, for the ones that don't believe me, well mad cow has been in the USA for decades undetected officially, but the late Richard Marsh documented way back, again, swept under the rug. Then in 2003 in December, the first case of BSE was finally documented, by accident. Then you had the next two cases that were documented in Texas and Alabama, but it took an act of Congress, literally, to get those finally documented, and when they were finally documented, they were atypical BSE or Bovine Amyloid Spongiform Encephalopathy (BASE), which when transmitted to humans is not vCJD or nvCJD, but SPORADIC CJD. Now you might ask yourself what about that mad cow feed ban of August 4, 1997, the year my mother died from the Heidenhain Variant of Creutzfeldt Jakob Disease (confirmed), well that ruminant to ruminant was merely a regulation on paper that nobody enforced. Just last month there was 10+ PLUS MILLION POUNDS OF BANNED BLOOD TAINTED MBM DISPERSED INTO COMMERCE, and there is no way the FDA will ever recover it. It will be fed out again. 2006 was a banner year for FDA mad cow protein fed out into commerce. Looks like 2007 will be also. Our federal Government has failed us at every corner when it comes to food safety. maybe your dog, your cat, your mom, your dad, your aunt, or your uncle, but again, who cares, there old and demented, just put them down, or put them away. It's hell getting old. ...END


Crushed heads (which inevitably involve brain and spinal cord material) are used to a limited extent but will also form one of the constituent raw materials of meat and bone meal, which is used extensively in pet food manufacturer...



http://www.bseinquiry.gov.uk/files/yb/1989/03/17004001.pdf




http://www.swnebr.net/newspaper/cgi-bin/articles/articlearchiver.pl?160273



http://newhopetoday.blogspot.com/2007/04/article-posted-04152007-91648-pm-human.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





http://betaamyloidcjd.blogspot.com/




re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease




http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html






Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518