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.
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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
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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.
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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
Thursday, February 26, 2009
Tuesday, August 26, 2008
Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007
FC4.3
Transmission of AA-amyloidosis: Similarities with Prion Disorders
Westermark, P Rudbeck laboratory, Department of Genetics and Pathology, Sweden
The systemic amyloidoses are characterized by widely spread amyloid deposits that can affect virtually every organ in the body. The precursor protein, which varies between different forms is produced at one or several locations, circulates with the plasma and is finally deposited as fibrils in the target organs by mechanisms yet to be determined. In one of the more common forms, systemic AA-amyloidosis, the substrate protein serum AA (SAA) is an acute phase reactant, with significant production only when certain proinflammatory signal substances are upregulated. A persistently high plasma concentration of SAA is a prerequisite for AA-amyloidosis to develop. AA-amyloidosis can easily be induced in many strains of mice by an inflammatory challenge, typically after a long lag phase. This phase is dramatically shortened by administration of amyloid fibrils extracted from an amyloidotic mouse, given intravenously, intra-nasally or given in the drinking water. The fibrillar extract is very potent, active down to pg of protein and facilitates amyloid formation even when given several months before an inflammation is induced. Also amyloid-like fibrils, produced in vitro from synthetic peptides have a clear effect, supporting the idea that the active principle is the misfolded and aggregated protein. AA-amyloidosis occurs in many avian and mammalian species. AA-fibrils from some, but not all species seed murine amyloidosis, showing a species barrier. AA-amyloidosis occurs in species, used as human food and may therefore be a risk factor. Consequently, AA-amyloidosis has similarity with prionoses, differing by the need of an upregulated production of the substrate SAA.
P03.139
Cellular Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein
Hooper, NM1; Parkin, ET1; Watt, NT1; Baybutt, H2; Manson, J2; Hussain, I3; Turner, AJ1 1University of Leeds, Institute of Molecular and Cellular Biology, UK; 2Roslin Institute, Neuropathogenesis Unit, UK; 3GlaxoSmithKline, Neurodegeneration Research, UK
Background: The normal cellular function of the prion protein (PrP), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD) in humans, remains enigmatic. Several studies have reported combinations of Alzheimer’s Disease (AD) and CJD neuropathology and the Val/Met129 polymorphism in the PrP gene has been identified as a risk factor for early-onset AD, leading to speculation that there may be some pathogenic connection between these two neurodegenerative conditions. The amyloid ß (Aß) peptides that cause AD are derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by the ß-secretase (BACE1) and the g-secretase complex. Aim: As both APP and PrP are cleaved by zinc metalloproteases of the ADAM family, we investigated whether PrP alters the proteolytic processing of APP. Results: Here we show that expression of PrP in SH-SY5Y cells dramatically downregulated the cleavage of APP by BACE1 and reduced the secretion of Aß peptides into the conditioned medium by >92%. Conversely, siRNA reduction of endogenous PrP in N2a cells led to an increase in secreted Aß. Furthermore, levels of Aß were significantly increased in the brains of PrP null mice as compared with wild type mice. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases, did not inhibit the BACE1 cleavage of APP. To investigate whether the Val/Met129 polymorphism in human PrPC would alter the production of Aß, brains from mice with the human PrP gene with MM or VV 129 genotypes were analysed. In the MM mice there was a significant increase in Aß in the brains as compared with the VV mice. In the brains of two strains (79A and 87V) of scrapie-infected mice there was a significant increase in Aß peptides as compared to uninfected mice. Conclusions: Together these data reveal a novel function for PrP in regulating the processing of APP through inhibition of BACE1. The increase in APP processing in cells expressing disease-associated forms of PrP and in scrapie-infected brains raises the possibility that the increase in Aß may contribute to the neurodegeneration observed in prion diseases. Funded by the Medical Research Council of Great Britain.
P03.140
Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein through Interaction with Glycosaminoglycans
Griffiths, HH; Parkin, ET; Watt, NT; Turner, AJ; Hooper, NM University of Leeds, Institute of Molecular and Cellular Biology, UK
Background: Proteolytic processing of the amyloid precursor protein (APP) by ßsecretase, BACE1, is the initial step in the production of the amyloid ß (Aß) peptide which is involved in the pathogenesis of Alzheimer’s disease. We have shown that the cellular prion protein (PrP) inhibits the cleavage of APP by BACE1 in cell and animal models. Aim: To investigate the mechanism by which PrP inhibits the action of BACE1. Results: Neither PrPdeltaGPI, which is not membrane attached, nor PrP-CTM, which is anchored by a transmembrane domain and is excluded from cholesterol-rich lipid rafts, reduced cleavage of APP, suggesting that to inhibit the BACE1 cleavage of APP PrP has to be localised to lipid rafts. Coimmunoprecipitation experiments demonstrated that PrP physically interacts with BACE1. However, PrP did not alter the activity of BACE1 towards a fluorogenic peptide substrate nor perturb the dimerisation of BACE1. Using constructs of PrP lacking either the octapeptide repeats or the 4 residues KKRP at the N-terminus of the mature protein (PrPdeltaN), we demonstrate that the KKRP sequence but not the octapeptide repeats, is essential for regulating the BACE1 cleavage of APP. As the KKRP sequence is known to participate in glycosaminoglycan (GAG) binding, we confirmed that PrPdeltaN did not bind to immobilised heparin. Addition of heparin to SH-SY5Y cells increased the amount of APP cleaved by BACE1 in a concentration-dependent manner and reduced the amount of BACE1 coimmunoprecipitated with PrP, suggesting that GAGs are required for PrP to interact with BACE1 and inhibit APP processing. Of a range of GAGs, including dextran sulphate, hyaluronic acid and chondroitin sulphate, investigated there was complete correlation between those that could restore BACE1 cleavage of APP in PrP expressing cells and those that bound PrP. Conclusion: These data suggest a possible mechanism by which PrP regulates the ßcleavage of APP is through the N-terminus of PrP interacting via GAGs with one or more of the heparin binding sites on BACE1 within a subset of cholesterol-rich lipid rafts, thereby restricting access of BACE1 to APP. Funded by the Medical Research Council of Great Britain.
P04.37
Comparison of the Neuropsychological Profile of Patients with Sporadic Creutzfeldt-Jakob Disease and Patients with Alzheimer’s
Krzovska, M1; Cepek, L1; Ratzka, P2; Döhlinger, S3; Uttner, I1; Wolf, Stefanie4; Irle, Eva4; Mollenhauer, Brit5; Kretzschmar, Hans A.6; Riepe, Matthias7; v. Arnim, Christine1; Otto, Markus1 1University of Ulm, Germany; 2Department of Neurology, Germany; 3University of Goettingen, Germany; 4University of Goettingen, Germany; 5Elena Klinik, Germany; 6LMU, Germany; 7University of Berlin, Germany
Background:To evaluate the neuropsychological profile of sCJD we administered the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) in order to determine if and how the sCJD-Subgroups (Met/Met, Met/Val, Val/Val) have different results in the item analysis of the ADAS-cog. Furthermore, we studied how the scores differ from that of patients with Alzheimer’s disease (AD). Methods:33 sCJD patients (11 with definite CJD and 22 with probable CJD) underwent neuropsychological testing with the ADAS-cog and Mini Mental State Exam (MMSE). Of these 31 were genotyped at the Codon 129 (11 Val/Val, 18 Met/Val and 2 Met/Met). The patients were matched in regards to sex and total ADAS-cog score with AD patients. The scores of the 11 ADAS-cog items were compared between the sCJD and the AD groups as well as between the sCJD-subgroups Met/Val and Val/Val and the AD group. Results:The ADAS-cog total score of the sCJD and AD groups was 22.6+/- 6.5, respectively. Regarding the single Item scores of the sCJD patient group and the AD patient group, there were statistically significant differences in the Items Constructional praxis, Word-finding difficulty in spontaneous speech and Spoken language ability. When comparing the sCJD subtypes with each other no statistically significant difference was found in the items. Conclusion: In the speech domain and constructional praxis there is indication of greater impairment in sCJD patients in general when compared with AD patients. A disturbance of the speech appears to be an important characteristic of the Met/Val and Val/Val subtypes of sCJD, and should therefore be the focus of special attention in future neuropsychological studies.
http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf
please see full text ;
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
http://betaamyloidcjd.blogspot.com/
re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
Terry S. Singeltary Sr. P.O. Box 42 Baycliff, Texas USA 77518
Transmission of AA-amyloidosis: Similarities with Prion Disorders
Westermark, P Rudbeck laboratory, Department of Genetics and Pathology, Sweden
The systemic amyloidoses are characterized by widely spread amyloid deposits that can affect virtually every organ in the body. The precursor protein, which varies between different forms is produced at one or several locations, circulates with the plasma and is finally deposited as fibrils in the target organs by mechanisms yet to be determined. In one of the more common forms, systemic AA-amyloidosis, the substrate protein serum AA (SAA) is an acute phase reactant, with significant production only when certain proinflammatory signal substances are upregulated. A persistently high plasma concentration of SAA is a prerequisite for AA-amyloidosis to develop. AA-amyloidosis can easily be induced in many strains of mice by an inflammatory challenge, typically after a long lag phase. This phase is dramatically shortened by administration of amyloid fibrils extracted from an amyloidotic mouse, given intravenously, intra-nasally or given in the drinking water. The fibrillar extract is very potent, active down to pg of protein and facilitates amyloid formation even when given several months before an inflammation is induced. Also amyloid-like fibrils, produced in vitro from synthetic peptides have a clear effect, supporting the idea that the active principle is the misfolded and aggregated protein. AA-amyloidosis occurs in many avian and mammalian species. AA-fibrils from some, but not all species seed murine amyloidosis, showing a species barrier. AA-amyloidosis occurs in species, used as human food and may therefore be a risk factor. Consequently, AA-amyloidosis has similarity with prionoses, differing by the need of an upregulated production of the substrate SAA.
P03.139
Cellular Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein
Hooper, NM1; Parkin, ET1; Watt, NT1; Baybutt, H2; Manson, J2; Hussain, I3; Turner, AJ1 1University of Leeds, Institute of Molecular and Cellular Biology, UK; 2Roslin Institute, Neuropathogenesis Unit, UK; 3GlaxoSmithKline, Neurodegeneration Research, UK
Background: The normal cellular function of the prion protein (PrP), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD) in humans, remains enigmatic. Several studies have reported combinations of Alzheimer’s Disease (AD) and CJD neuropathology and the Val/Met129 polymorphism in the PrP gene has been identified as a risk factor for early-onset AD, leading to speculation that there may be some pathogenic connection between these two neurodegenerative conditions. The amyloid ß (Aß) peptides that cause AD are derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by the ß-secretase (BACE1) and the g-secretase complex. Aim: As both APP and PrP are cleaved by zinc metalloproteases of the ADAM family, we investigated whether PrP alters the proteolytic processing of APP. Results: Here we show that expression of PrP in SH-SY5Y cells dramatically downregulated the cleavage of APP by BACE1 and reduced the secretion of Aß peptides into the conditioned medium by >92%. Conversely, siRNA reduction of endogenous PrP in N2a cells led to an increase in secreted Aß. Furthermore, levels of Aß were significantly increased in the brains of PrP null mice as compared with wild type mice. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases, did not inhibit the BACE1 cleavage of APP. To investigate whether the Val/Met129 polymorphism in human PrPC would alter the production of Aß, brains from mice with the human PrP gene with MM or VV 129 genotypes were analysed. In the MM mice there was a significant increase in Aß in the brains as compared with the VV mice. In the brains of two strains (79A and 87V) of scrapie-infected mice there was a significant increase in Aß peptides as compared to uninfected mice. Conclusions: Together these data reveal a novel function for PrP in regulating the processing of APP through inhibition of BACE1. The increase in APP processing in cells expressing disease-associated forms of PrP and in scrapie-infected brains raises the possibility that the increase in Aß may contribute to the neurodegeneration observed in prion diseases. Funded by the Medical Research Council of Great Britain.
P03.140
Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein through Interaction with Glycosaminoglycans
Griffiths, HH; Parkin, ET; Watt, NT; Turner, AJ; Hooper, NM University of Leeds, Institute of Molecular and Cellular Biology, UK
Background: Proteolytic processing of the amyloid precursor protein (APP) by ßsecretase, BACE1, is the initial step in the production of the amyloid ß (Aß) peptide which is involved in the pathogenesis of Alzheimer’s disease. We have shown that the cellular prion protein (PrP) inhibits the cleavage of APP by BACE1 in cell and animal models. Aim: To investigate the mechanism by which PrP inhibits the action of BACE1. Results: Neither PrPdeltaGPI, which is not membrane attached, nor PrP-CTM, which is anchored by a transmembrane domain and is excluded from cholesterol-rich lipid rafts, reduced cleavage of APP, suggesting that to inhibit the BACE1 cleavage of APP PrP has to be localised to lipid rafts. Coimmunoprecipitation experiments demonstrated that PrP physically interacts with BACE1. However, PrP did not alter the activity of BACE1 towards a fluorogenic peptide substrate nor perturb the dimerisation of BACE1. Using constructs of PrP lacking either the octapeptide repeats or the 4 residues KKRP at the N-terminus of the mature protein (PrPdeltaN), we demonstrate that the KKRP sequence but not the octapeptide repeats, is essential for regulating the BACE1 cleavage of APP. As the KKRP sequence is known to participate in glycosaminoglycan (GAG) binding, we confirmed that PrPdeltaN did not bind to immobilised heparin. Addition of heparin to SH-SY5Y cells increased the amount of APP cleaved by BACE1 in a concentration-dependent manner and reduced the amount of BACE1 coimmunoprecipitated with PrP, suggesting that GAGs are required for PrP to interact with BACE1 and inhibit APP processing. Of a range of GAGs, including dextran sulphate, hyaluronic acid and chondroitin sulphate, investigated there was complete correlation between those that could restore BACE1 cleavage of APP in PrP expressing cells and those that bound PrP. Conclusion: These data suggest a possible mechanism by which PrP regulates the ßcleavage of APP is through the N-terminus of PrP interacting via GAGs with one or more of the heparin binding sites on BACE1 within a subset of cholesterol-rich lipid rafts, thereby restricting access of BACE1 to APP. Funded by the Medical Research Council of Great Britain.
P04.37
Comparison of the Neuropsychological Profile of Patients with Sporadic Creutzfeldt-Jakob Disease and Patients with Alzheimer’s
Krzovska, M1; Cepek, L1; Ratzka, P2; Döhlinger, S3; Uttner, I1; Wolf, Stefanie4; Irle, Eva4; Mollenhauer, Brit5; Kretzschmar, Hans A.6; Riepe, Matthias7; v. Arnim, Christine1; Otto, Markus1 1University of Ulm, Germany; 2Department of Neurology, Germany; 3University of Goettingen, Germany; 4University of Goettingen, Germany; 5Elena Klinik, Germany; 6LMU, Germany; 7University of Berlin, Germany
Background:To evaluate the neuropsychological profile of sCJD we administered the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) in order to determine if and how the sCJD-Subgroups (Met/Met, Met/Val, Val/Val) have different results in the item analysis of the ADAS-cog. Furthermore, we studied how the scores differ from that of patients with Alzheimer’s disease (AD). Methods:33 sCJD patients (11 with definite CJD and 22 with probable CJD) underwent neuropsychological testing with the ADAS-cog and Mini Mental State Exam (MMSE). Of these 31 were genotyped at the Codon 129 (11 Val/Val, 18 Met/Val and 2 Met/Met). The patients were matched in regards to sex and total ADAS-cog score with AD patients. The scores of the 11 ADAS-cog items were compared between the sCJD and the AD groups as well as between the sCJD-subgroups Met/Val and Val/Val and the AD group. Results:The ADAS-cog total score of the sCJD and AD groups was 22.6+/- 6.5, respectively. Regarding the single Item scores of the sCJD patient group and the AD patient group, there were statistically significant differences in the Items Constructional praxis, Word-finding difficulty in spontaneous speech and Spoken language ability. When comparing the sCJD subtypes with each other no statistically significant difference was found in the items. Conclusion: In the speech domain and constructional praxis there is indication of greater impairment in sCJD patients in general when compared with AD patients. A disturbance of the speech appears to be an important characteristic of the Met/Val and Val/Val subtypes of sCJD, and should therefore be the focus of special attention in future neuropsychological studies.
http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf
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Alzheimer's and CJD
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Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
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re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
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Terry S. Singeltary Sr. P.O. Box 42 Baycliff, Texas USA 77518
Saturday, May 17, 2008
Are cheetahs on the run from prion-like amyloidosis?
Are cheetahs on the run from prion-like amyloidosis?
Byron Caughey* and Gerald S. Baron* Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 598940
The misfolding and aggregation of proteins is often an accident waiting to happen. Consequently, organisms have developed sophisticated chaperone and quality-control systems to limit abnormal protein interactions and the accumulation of toxic aggregates (1). However, sometimes these systems can be overwhelmed, and diseases, namely protein misfolding diseases, can result. One such disease, amyloid protein A (AA) amyloidosis, is wreaking havoc in the captive cheetah population, complicating efforts to rescue this endangered species from extinction (2, 3). One key to managing this fatal disease in cheetahs is to understand why it is so prevalent. Most cases of AA amyloidosis in mammals appear to occur spontaneously, usually as a result of chronic inflammation or genetic peculiarities that predispose the organism to the deposition of serum amyloid A (SAA) protein in fibrillar deposits called amyloid (Fig. 1). In this issue of PNAS, Zhang et al. (4) report that AA amyloid is excreted in the feces of cheetahs with AA amyloidosis and that this fecal amyloid can in turn promote a similar disease in mice. These results suggest that cheetah AA amyloidosis may not be simply a spontaneous disease, but also a natural prion-like, transmissible protein misfolding disease. Prions are protein-based infectious agents or elements of inheritance that, unlike conventional pathogens, lack agent-specific nucleic acid genomes (5, 6). Prions have been described in both mammals (e.g., bovine spongiform encephalopathy and Creutzfeldt–Jakob disease) and fungi ([URE3], [PSI], and [Het-s]). Replication of prions requires a self-propagating modification of an otherwise non-prion host protein. Usually the mechanism involves the recruitment of the normal form of the protein into a growing amyloid-like prion aggregate. In many cases the presence of prions is a disease state, but some prions play normal physiological roles (7). Although amyloid-like protein aggregation is typical of many important protein misfolding diseases, including Alzheimer’s disease and type 2 diabetes, most of these diseases are not known to be naturally transmissible or heritable because of transfer of the amyloid. However, experimental inoculations of amyloid preparations can enhance amyloidosis in nai¨ve mice that are strongly primed for the development of amyloidosis (8, 9). This suggests that there is potential for amyloidoses, in general, and AA amyloidosis specifically, to be transmissible and, hence, prion-like. For such transmissions to be significant in the real world, there must be practical routes of transmission and the potential for inducing disease in natural, rather than artificially primed, hosts. The shedding of AA amyloid into the feces of cheetahs suggests a potential route of transmission (Fig. 1) (4). Although the fecal amyloid can promote amyloidosis on i.v. inoculation into mice, this is only true in mice that were primed for amyloidosis by injections of an inflammatory chemical (silver nitrate) that dramatically boosts serum SAA levels. The silver nitrate treatment alone causes spontaneous amyloidosis in these mice, albeit at a slower pace than when the mice are inoculated with exogenous amyloid. Thus, it remains to be determined whether fecal amyloid can actually initiate, rather than enhance, amyloidosis in either mice or cheetahs and, if so, by what route of inoculation. One possible mode of entry would be oral because AA amyloid can be active in primed mice when administered orally as well as intravenously (9, 10). Another potential route would be direct inoculation of fecal amyloid into the blood stream through cuts or abrasions. It should be noted that Zhang et al. (4) inoculated mice with highly concentrated preparations of fecal amyloid. Hence, it is unknown whether amyloid concentrations in feces would allow transmission to nai¨ve recipients by any peripheral route. If fecal amyloid can be transmitted to other captive cheetahs, what makes these animals so susceptible to AA amyloidosis? The fact that mice can be primed for AA amyloidosis by inflamm tory stimuli raises the possibility that inflammation is also important in cheetahs. Indeed, inflammatory diseases are prominent in captive cheetahs with AA amyloidosis, and a number of precipitating factors, including chronic infections, diet, and stress, have been identified (2, 3). Other possibilities include genetic predispositions of cheetahs to AA amyloidosis because of their SAA sequence or expression level. Interestingly, a gene polymorphism has been identified in captive cheetahs that flanks the SAA1 gene and strongly affects its transcriptional induction in response to inflammation (11). Expression of other proteins can also profoundly enhance susceptibility of animals to AA amyloidosis, as shown by modulation of pentraxin levels in hamsters (12). The genetic homogeneity of captive cheetahs may enhance these susceptibility problems (11, 13), but does not appear to be the sole issue (3). The very factors that might make cheetahs susceptible to exogenous AA amyloid ‘‘infections’’ should also potentiate spontaneous AA amyloidosis in these animals. There is precedent for this in the spontaneous amyloidosis that occurs in silver nitrate-primed mice. By analogy, it remains possible that the high incidence of AA amyloidosis in cheetahs is caused by spontaneous disease exacerbated by the inflammatory stimuli, stresses, and inbreeding of captivity rather than exposure to fecal amyloid. Further studies will be required to resolve these questions. AA amyloidosis susceptibility issues may have serious implications for cheetah conservation efforts. If the objective is to rescue the wild cheetah population by releasing cheetahs bred in captivity, then it will be important to know the impact of releasing amyloidotic animals into the wild. Will AA amyloidosis continue to progress and affect the survival of released cheetahs? Can the disease be spread to wild cheetahs? One encouraging observation is that, relative to captive cheetahs, wild Namibian cheetahs are remarkably free of disease, including inflammatory diseases such as AA amyloidosis and gastritis (3). Perhaps lower chronic levels of inflammation, and hence serum SAA levels, make them less susceptible than captive cheetahs to AA amyloid shed by other animals. Although major questions remain about the etiology of AA amyloidosis in captive cheetahs, it may be wise to take measures to limit exposure of cheetahs to potential sources of amyloid ‘‘infectivity.’’ The demonstration that cheetah AA amyloid is active in mice indicates that there is cross-species promiscuity in its amyloid-inducing capacity. This promiscuity might also work in reverse, rendering cheetahs susceptible to AAamyloid- laden tissues of other species that might be fed to them. Interestingly, foie gras was recently shown to contain AA amyloid that could accelerate amyloidosis when fed to mice (9). Thus, consideration of a variety of potential sources of exposure for cheetahs seems warranted. Furthermore, if chronic inflammation enhances disease susceptibility, then anti-inflammatory therapies may be helpful. Is AA amyloidosis in cheetahs a prion disease? The answer depends on whether AA amyloidosis in captive cheetahs is caused by spontaneous disease or transmission of amyloid between animals. Environmental influences on AA amyloidosis epidemiology could be due to the presence of either ‘‘infectious’’ amyloid, a prion-like etiology, or to factors that enhance the incidence of spontaneous disease, i.e., a non-prion etiology. Even if transfer of AA amyloid between cheetahs enhances AA amyloidosis, the question would remain as to whether the transferred amyloid initiates the disease de novo or merely accelerates ongoing disease. The latter scenario would place AA amyloidosis into a gray area with respect to the basic prion concept. In this instance, prion transmission would affect the kinetics of the disease without actually initiating it. Regardless of prion semantics, there could be practical consequences of such kinetic phenomena in both animals and humans. For instance, recent studies have shown that in ection of -amyloid can enhance Alzheimer’s-like amyloidosis in transgenic mice (14). This raises the possibility that inadvertent transfer of -amyloid from one person to another could accelerate the neurodegenerative process to the point where it becomes Alzheimer’s disease as opposed to normal aging. In this example, as well as in cheetah AA amyloidosis and many other protein misfolding diseases, the basic problem is likely the outpacing of an organism’s protein quality control mechanisms. This may sometimes be more a problem of the rate, rather than of the instigation, of protein misfolding.
Fig. 1. Diagram of AA amyloid formation and the potential prion-like transmission of AA amyloidosis by fecal shedding and oral uptake of the amyloid. The photo shows an example of Congo red-stained AA amyloid fibril deposits in hamster liver tissue (courtesy of John Coe, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases).
ACKNOWLEDGMENTS. This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. 1. Balch WE. Morimoto RI, Dillin A, KellyJW(2008) Adapting proteostasis for disease intervention. Science 319:916–919. 2. Papendick RE, Munson L, O’Brien TD, Johnson KH (1997) Systemic AA amyloidosis in captive cheetahs (Acinonyx jubatus). Vet Pathol 34:549–556. 3. MunsonL, et al. (2005) Extrinsic factors significantly affect patterns of disease in free-ranging and captive cheetah (Acinonyx jubatus) populations. J Wildl Dis 41:542–548. 4. Zhang B, et al. (2008) Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease. Proc Natl Acad Sci USA 105:7263–7268. 5. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383. 6. Wickner RB, et al. (2004) Prion genetics: New rules for a new kind of gene. Annu Rev Genet 38:681–707. 7. Coustou V, Deleu C, Saupe S, Begueret J (1997) The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. Proc Natl Acad Sci USA 94:9773–9778. 8. Kisilevsky R, Boudreau L (1983) Kinetics of amyloid deposition. I. The effects of amyloid-enhancing factor and splenectomy. Lab Invest 48:53–59. 9. Solomon A, et al. (2007) Amyloidogenic potential of foie gras. Proc Natl Acad Sci USA 104:10998–11001. 10. Lundmark K, et al. (2002) Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc Natl Acad Sci USA 99:6979–6984. 11. Zhang B, et al. (March 28, 2008) Characterization of the cheetah serum amyloid A1 gene: Critical role and functional polymorphism of a cis-acting element. J Hered, 10.1093/jhered/esn015. 12. Coe JE, Ross MJ (1990) Amyloidosis and female protein in the Syrian hamster: Concurrent regulation by sex hormones. J Exp Med 171:1257–1267. 13. O’Brien SJ, et al. (1985) Genetic basis for species vulnerability in the cheetah. Science 227:1428 – 1434. 14. Meyer-Luehmann M, et al. (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784. 7114 www.pnas.orgcgidoi10.1073pnas.0803438105 Caughey and Baron
http://www.pnas.org/cgi/reprint/0803438105v1?etoc
Monday, May 12, 2008
Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease
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Alzheimer's and CJD
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Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer’s disease facts and figures
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Original Paper
Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
Laura Debatina, Johannes Strefferb, Markus Geissenc, Jakob Matschkec, Adriano Aguzzia, Markus Glatzela, c
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Sunday, April 27, 2008 re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease Greetings,
I thought this most important research by Aguzzi et al 'Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease' most important, and thought further reading of this study should be at hand.
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
Draft Factual Account #5
10. On 28 June 1986 Mr Jeffrey examined tissue sections taken from the brain of a nyala which had been kept at Marwell Zoo.(S Jeffrey para 6; YB86/7.8/1.1 ) This examination, and subsequent consideration of the report, are described in the CVL DFA.
51. On 10 June 1987 Mr Bradley sent a BSE update to Dr Watson. It discussed, amongst other things, the nyala case and subsequent paper, the work of Mr Wilesmith, the upcoming BCVA meeting and the work of Dr Kimberlin.(YB 87/6.10/1.1 )
63. On 22 June 1987 Mr Bradley sent a memo to Mr Wells detailing actions taken to date. It noted that publication has been discussed with the CVO and halted and that there were now at least 9 suspect herds and a case in a gemsbok at Marwell.(YB 87/6.22/2.1 )
74. On 1 July 1987, Mr Bradley wrote to Mr Jeffrey to tell him that his article on spongiform encephalopathy in a nyala was not authorised for publication, and that while he made comparisons with scrapie, the CVO was unlikely to give his approval.(YB87/6.29/3.1; YB87/7.1/2.1; YB87/7.1/3.1-3.10 ) This is further discussed in the CVL DFA.
153. On 11 December 1987, Mr Jeffrey's paper on the nyala was submitted for publication in the journal Veterinary Pathology. The paper had first been drafted the paper in autumn 1986. (S 64 Jeffrey para 10) The title of the paper was changed from 'A scrapie-like disorder in a nyala' to 'A spongiform encephalopathy in a nyala.' Other references to scrapie were also amended.( S Jeffrey para 10; S 65 Wells para 55; YB87/11.11/2.1; YB87/11.17/3.1; YB87/11.23/2.1. )
Spongiform encephalopathy in a nyala (Tragelaphus angasi).
Vet Pathol 1988 Sep;25(5):398-9 Jeffrey M, Wells GA Lasswade Veterinary Laboratory, Midlothian.
166. In January 1988, Mr Wilesmith was informed of the June 1987 case of SE in the gemsbok. He discovered from the Winchester VIC that both the >nyala and the gemsbok had received rations containing MBM and this provided further support for his hypothesis.( S Wilesmith para. 37)
Draft Factual Account #4
28. On 28 June 1986 Dr Jeffrey examined tissue sections taken from the brain of a nyala which had been kept at Marwell Zoo. (S Jeffrey para 6; YB86/7.8/1.1 ) The nyala had shown unusual nervous symptoms two weeks prior to being put down on welfare grounds. These symptoms included 'weaving with the head and neck, holding the head on its side and frequent nibbling near the tailbone.'(YB86/6.23/1.1 ) The sections were originally necropsied by Mr Geoff Holmes at the Winchester VIC.(YB86/5.29/1.1; YB86/6.18/1.1 ) The nyala (tragelaphus angasi) is not an antelope but belongs to the same family (species group) as cattle.
29. Dr Jeffrey observed that the brain showed taxonomic lesions of spongiform encephalopathy and that the similarity of the lesions to natural sheep scrapie was striking, and indeed he thought that in comparison to natural sheep scrapie the lesions were particularly florid.(YB86/7.2/1.1; S Jeffrey para 9 ) The sites (neuroanatomical location) and cellular location (grey matter neuropil and neuronal cytoplasmic vacuolation) were distinctive and characteristic of the TSEs. Dr Jeffrey sent a slide of the nyala brain to Dr Richard Kimberlin at the NPU in the latter quarter of 1986 who 'vividly recollect[ed] seeing the results down the microscope because the pathology was so striking'.(YB 98/11.18/1.1 )
30. Following a field visit to Marwell Zoo on 21 July 1986,(YB86/7.24/1.1 ) a report was compiled by Mr Holmes at Winchester VIC and a scientific paper prepared for publication in a journal.(S Jeffrey para 10 ) Dr Jeffrey conferred with Mr Wells, his line manager at the CVL, in the preparation of the paper.(S Jeffrey para 9; S Wells 1st para 55 ) Dr Jeffrey was not sure of the exact date he submitted the paper to the Animal Health and Veterinary Group (AHVG) for publication but said it was some time in Autumn 1986.(S Jeffrey para 10; YB86/11.00/1.1 ) Dr Jeffrey did not form any conclusions about the origins of the disease in this animal, but he discussed the case with the CVL Epidemiology Department, and they agreed to keep a 'watching brief' on the situation.(S Wilesmith para 11)
89. On 17 June 1987 the Annual Report of the CVO for 1986 was published, having been submitted for publication on 1 June 1987.( M24 Tab 2 at 69 ) The Report described the discovery of a 'Scrapie-like disease in a captive nyala' and noted that 'Transmissible spongiform encephalopathies have been reported in man, sheep and goats (scrapie), mule deer and mink.'
91. On 19 June 1987 Mr Bradley sent Dr Watson a BSE Update. Amongst other things it was noted:(YB 87/6.19/3.1-3.2 )
"The final draft Vet Rec paper has been prepared and submitted for authority to publish. This has been rejected by CVO whilst scrapie is mentioned. For this and other reasons the paper is temporarily withdrawn until further information is available"
92. On 19 June 1987 Dr S.H. Done diagnosed spongiform encephalopathy in a gemsbok from Marwell Park.(YB87/6.19/3.2; YB876.8/3.1; YB87/6.10/3.1; YB87/6.25/1.1 ) This was the zoo was from which the SE-infected nyala had come. While the nyala was from the same species group as cattle, the gemsbok is an African antelope.
100. On 1 July 1987 Mr Bradley wrote to Dr Jeffrey to tell him that his article on spongiform encephalopathy in a nyala was not authorised for publication, and that while he made comparisons with scrapie, the CVO was unlikely to give his approval.(YB87/7.1/3.2; YB87/6.29/3.1; YB87/7.1/2.1 ) The initial title of the paper was 'Scrapie-like disorder in a nyala'.( S Jeffrey para 12 ) At the request of Tolworth, the title of the paper was eventually changed to 'Spongiform encephalopathy in a nyala'.( YB87/11.00/1.1 ) Because of the original references to the scrapie-like nature of the disorder the paper was delayed for publication and was not published until September 1988.( J/VP/25/398 ) Dr Jeffrey told the BSE Inquiry that he resisted the move to alter his paper because it 'would have been negligent to try and publish that without a reference to scrapie'.(T25 at 32 )
157. On 17 November 1987 Mr Bradley minuted Dr Jeffrey noting that the title to his nyala paper was likely to be unacceptable to "senior management" for "veterinary political reasons". He also recommended that where comparisons were made with scrapie the emphasis ought to be altered.(YB 87/11.17/1.1 )
433. On 23 October 1989 Dr Watson told Mr Wells that the CVL were to supply material from the kudu and nyala to the NPU for transmission to mice. Dr Watson said this was an important transmission experiment designed to establish the relationship between the disease in zoo animals and cattle.(S Watson 1st para 134 ) Mr Bradley provided Dr Watson with a list of tissues that were to be sent to the NPU on 24 November 1989.(YB89/10.24/4.1 )
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BSE Inquiry site Draft Factual Account 13 extracts related to zoo animals:
19. On 24 January 1990 Mr Bradley sent to Dr Watson a summary of the main points of a meeting held with the Minister the same day.(20) The minute noted: "The Minister played Devil's advocate in relation to: ... 5. MBM exports unethical. All should be labelled & a letter should be sent to all countries to which MBM was exported should be sent." [No such letter was sent.]
28. By 12 February 1990 the nyala and kudu tissues and the placenta had been inoculated into mice at the NPU.(33) After his investigations into the alimentary tract, ... Mr Bradley said in a minute dated 12 February 1990 that:(36) "It is very clear that it is important to initiate studies now in a much wider range of tissues and in multiple specimens than can be accommodated in the annual quota of 30 for the next two years." Mr Bradley attached a table showing the progress of infectivity studies:..fixed nyala brain, fixed kudu brain, buffy coat.
57. On 17 September 1990 Mr Bradley circulated a minute with regards to an offer by Dr Schellekers of the Netherlands to collaborate on attempting to transmit BSE to chimpanzees.(YB90/9.17/1.1) Mr Wells and Dr Rosalind Ridley, who was conducting the marmoset experiment, told Mr Bradley that they did not feel there was any greater justification for an attempted transmission in chimpanzees than marmosets.(S Bradley 3rd para 40 ) Mr Bradley passed on this view to the CVO.(YB90/9.23/1.1; YB90/9.26/3.1 ). [This is ignorant beyond belief.]
67. In Spring 1991 Mr McGill performed a review of 200 brains that had, using the obex histopathological method, been deemed BSE-negative.(110) This diagnostic approach, that had been developed for use within the VIS, used a single section from the medulla to look for spongiform change. In his review Mr McGill examined other parts of the brain.(111) In his statement to the BSE Inquiry Mr McGill said:
Upon closer examination, three of the 200 'BSE-negative' brains proved positive for spongiform changes diagnostic of BSE.(112) This represents an overall diagnostic accuracy of 99.85%, exceeding the 99.6% previously published for the same standard diagnostic technique. Despite this, at the behest of MAFF managers, the emphasis of the study and its provisional title had to be changed, from accurately representing the whole negative 10%, to a study examining this 10% minus any mention whatsoever of BSE-affected cattle going undiagnosed. I therefore had to reluctantly locate and analyse three new BSE-negative suspect brains.(113)
76. In mid-1991 it was decided that a proposed survey of 300 deer brains would proceed.(124) As with the hound survey, there were difficulties in collecting the material in a manner optimal for histopathological examinations.(See YB92/11.4/2.1) During the period 1986 to 1996, 26 deer brains were referred for examination to the Consultant Pathology Unit at the CVL, but none of these showed evidence of an SE.
103. On 16 July 1992 a meeting was held at CVL to discuss the research proposals relating to the studies on SEs in a greater kudu at a zoo. (S Bradley 3rd para 65 ) Three main experiments were proposed: to determine the distribution of agent in tissues; to study the epidemiology; and to strain type isolates from a brain of a new case of spongiform encephalopathy. Formal proposals were later drawn up and Mr Bradley became the Project Officer for the experiments.
108. Mr Bradley and Mr Dawson met staff at London Zoo on 23 March 1993 to discuss tissue selection for the proposed transmission studies on BSE-infected kudu material.(166) The Zoo did not want to keep the kudu, but moving them to the CVL was ruled out because of inadequate facilities to care for them. The investigations into the distribution of the SE agent in various tissues began in June 1993.
121. On 9 October 1993 Mr Wilesmith and others published a paper on the additional cases of TSE in the herd of greater kudu at London Zoo.(S Wilesmith 2nd para 95 ) On the basis of feeding histories, the authors concluded that horizontal transmission had occurred. However, subsequent investigations based at the zoo revealed that the affected animals were most likely to have been infected from the feedborne source.
143. On 3 July 1994 Mr Bradley was informed that two more kudu were to be culled.( Bradley 3rd para 86 ) He visited the London Zoo on 21 July 1994 to review the progress of the studies on TSEs in zoo animals. Necropsies were to be carried out on the kudu and tissues collected for further transmission studies. At this stage the mice that had been inoculated with kudu tissues in August and September 1993 had not succumbed to spongiform encephalopathy. The Zoo authorities wanted to move the kudu because of the possibility of bad publicity.(YB95/2.10/1.6) This was discussed at a SEAC meeting on 2 February 1995. The meeting agreed that the risk to Zoo visitors was minuscule or non-existent. Mr Bradley's case control study indicated that infected feed was the most probable cause of the BAB kudu SE cases.
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46. On 28 June 1990 Mr Bradley informed Mr Wells that a survey of hounds was to commence.(68) The hound survey arose because the Tyrrell Committee had recognised that domestic pets might prove susceptible to the unconventional agent of BSE and recommended monitoring the health of animals fed offal, carcases or meat and bone meal.(M11a Tab 8 )
47. A total of 444 hound brains of mixed breeds from 101 kennels across the United Kingdom were collected and examined. Histopathological changes consistent with a florid spongiform encephalopathy similar to that reported in cats was not observed. However, the report of the survey identified serious flaws in the survey's design. Mr Wells said in a minute to Mr Bradley in October 1991 that 'the survey as designed has little to offer scientifically'.(YB91/10.17/1.1)
54. On 20 August 1990 Mr Wells confirmed the parenteral transmission of BSE to a pig.(YB90/7.20/2.1) The pig was inoculated in February/March of 1989 and was slaughtered in July 1990.(S Wells 2nd para 40) An interim report was prepared for SEAC(84) and a press conference was held on 24 September 1990 to announce the parenteral transmission of BSE to pigs.(85) The transmission of BSE to pigs was a major factor in the ban on SBOs being extended to all animal feed. Experiments were also conducted by orally dosing pigs with BSE infected material but when the pigs were killed after seven years they were not found to be incubating the disease.(S Wells 2nd para 40 )
55. By August 1990 a total of 10 cases of FSE in domestic cats had been confirmed.(S Wilesmith 2nd para 109 ) Mr Wilesmith designed a questionnaire to be completed by the veterinarians who clinically identified FSE for the purposes of an epidemiological investigation. In addition to this investigation, the University of Bristol was subsequently granted a MAFF contract for a study in collaboration with the NPU to ascertain whether the condition in cats was transmissible to mice and, if so, to undertake strain typing of the agent.(S Wells 2nd para 104; YB 92/6.19/5.1 ) Mr Wells was appointed Project Officer to monitor the study. When the study was completed it showed that the disease in cats was transmissible and that similarities in the biological characteristics of FSE and BSE on transmission to mice indicated that the two diseases probably arose from a common source.(J/VR/134/449 )
64. In February 1991 Mr Mark Robinson began studies on the transmission of BSE to mink.(S Wilesmith 2nd paras 117-118 ) This study was done in collaboration with the United States Department of Agriculture (USDA), the Agricultural Research Service (ARS), and the Department of Veterinary Science at the University of Wisconsin, USA. The results of this study were discussed at the 10th CVL/NPU BSE R&D meeting held on 27 April 1993.(YB93/4.27/1.1) The results indicated that mink were susceptible to BSE, and in contrast to previous attempts to transmit scrapie to the species, were susceptible by the oral route of challenge.(J/JVIR /75/2151)
99. On 11 April 1992 Mr Bradley prepared a paper for the Lamming Expert Committee on Animal Feedingstuffs.(153) Some of the areas covered in the paper were tallow, the danger of BSE to pigs, the effect of the species barrier, tissue infectivity of lambs and calves, scrapie incidence and the danger of dogs developing SEs.
116. In July 1993 studies involving the oral exposure of pigs to scrapie were started the CVL.(179) Such studies were recommended by the expert committee on feedingstuffs chaired by Professor Lamming, because it was found that pigs had been orally exposed not only to BSE but also to scrapie. The pigs were orally exposed to scrapie-infected brain material in November 1993 and while the experiment remains in progress, no pigs have been shown to have developed the disease to date.
123. In December 1993 Dr Ken Charlton of the Animal Disease Research Institute, Nepean, Ontario, Canada, visited the CVL bringing material from a suspect case of BSE in Canada. The CVL confirmed that the case was a BSE case and reported it to the Canadian authorities.(189) in 1994.
152. On 13-16 February 1995 ... ...BSE to pigs - Further work to clarify the finding of non-specific vacuolation in the brains of control pigs was needed.
...BSE to chickens - Sub-passage in chickens and mice of various tissues from experimentally infected birds was needed to clarify the findings of neurological signs without neuropathology in inoculated birds.
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bibliography:
Vet Rec 1997 Sep 13;141(11):270-1 Baron-T, Belli-P Madec-J-Y Moutou-F Vitaud-C Savey-M Spongiform encephalopathy in an imported cheetah in France. CNEVA-Lyon, Laboratoire de Pathologie Bovine, France.
Proc Soc Exp Biol Med 1996 Apr;211(4):306-22 Narang H Origin and implications of bovine spongiform encephalopathy. [tiger]
Vet Rec. 1994 Nov 12;135(20):488. Benbow G. Spongiform encephalopathies in zoo animals. comment
Vet Rec 1994 Oct 29;135(18):440 Swainston J. comment
Vet Rec 1994 Sep 24;135(13):296-303 Kirkwood JK, Cunningham AA Epidemiological observations on spongiform encephalopathies
Vet Rec 1994 Feb 12;134(7):167-8 Kirkwood JK, Cunningham AA, Austin AR, Wells GA, Sainsbury AW Spongiform encephalopathy in a greater kudu
Vet Rec. 1993 Oct 9;133(15):360-4. Kirkwood JK, et al. Spongiform encephalopathy in a herd of greater kudu
Vet Rec. 1993 Jan 16;132(3):68. Cunningham AA, et al. Transmissible spongiform encephalopathy in greater kudu
Vet Rec. 1992 Nov 7;131(19):431-4. Willoughby K, et al. Spongiform encephalopathy in a captive puma
Aust Vet J 1992 Jul;69(7):171 Peet RL, Curran JM Spongiform encephalopathy in an imported cheetah
Vet Rec 1992 Apr 25;130(17):365-7 Kirkwood JK, Wells GA, Cunningham AA, Jackson SI, Scott AC, Dawson M, Wilesmith JW Scrapie-like encephalopathy in a greater kudu
Acta Neuropathol (Berl) 1992;84(5):559-69 Jeffrey M, Scott JR, Williams A, Fraser H Ultrastructural features of spongiform encephalopathy
Vet Rec. 1991 Oct 5;129(14):320 Synge BA, et al. Spongiform encephalopathy in a Scottish cat.
Vet Rec 1991 Sep 14;129(11):233-6 Wyatt JM, Pearson GR, Naturally occurring scrapie-like s
Vet Rec. 1991 Jun 1;128(22):532. Pearson GR, et al. Feline spongiform encephalopathy.
Vet Rec. 1991 Mar 30;128(13):311. Kock R. Spongiform encephalopathies in ungulates.
Vet Rec. 1991 Feb 2;128(5):115. Gibson PH. Spongiform encephalopathies in ungulates. comment
Vet Rec 1990 Dec 15;127(24):586-8 Leggett MM, Dukes J, Pirie HM A spongiform encephalopathy in a cat.
Done JT. Vet Rec. 1990 Nov 10;127(19):484. Spongiform encephalopathy in pigs.
Vet Rec. 1990 Oct 27;127(17):418-20. Kirkwood JK, et al. Spongiform encephalopathy in an arabian oryx (Oryx leucoryx) and a greater kudu.
Vet Rec. 1990 Sep 29;127(13):338. Dawson M, et al. Primary parenteral transmission of bovine spongiform encephalopathy to the pig.
Vet Rec. 1990 May 19;126(20):513 no authors listed Spongiform encephalopathy in a cat.
Vet Rec 1990 May 12;126(19):489-90 Gibson PH Spongiform encephalopathy in an eland.
Nature. 1990 Mar 15;344(6263):183 Aldhous P. Antelopes die of "mad cow" disease.
Vet Rec 1990 Apr 21;126(16):408-9 Fleetwood AJ, Furley CW Spongiform encephalopathy in an eland.
Vet Pathol. 1988 Sep;25(5):398-9 Jeffrey M, Wells GA Spongiform encephalopathy in a nyala (Tragelaphus angasi) Lasswade Veterinary Laboratory, Midlothian
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
Byron Caughey* and Gerald S. Baron* Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 598940
The misfolding and aggregation of proteins is often an accident waiting to happen. Consequently, organisms have developed sophisticated chaperone and quality-control systems to limit abnormal protein interactions and the accumulation of toxic aggregates (1). However, sometimes these systems can be overwhelmed, and diseases, namely protein misfolding diseases, can result. One such disease, amyloid protein A (AA) amyloidosis, is wreaking havoc in the captive cheetah population, complicating efforts to rescue this endangered species from extinction (2, 3). One key to managing this fatal disease in cheetahs is to understand why it is so prevalent. Most cases of AA amyloidosis in mammals appear to occur spontaneously, usually as a result of chronic inflammation or genetic peculiarities that predispose the organism to the deposition of serum amyloid A (SAA) protein in fibrillar deposits called amyloid (Fig. 1). In this issue of PNAS, Zhang et al. (4) report that AA amyloid is excreted in the feces of cheetahs with AA amyloidosis and that this fecal amyloid can in turn promote a similar disease in mice. These results suggest that cheetah AA amyloidosis may not be simply a spontaneous disease, but also a natural prion-like, transmissible protein misfolding disease. Prions are protein-based infectious agents or elements of inheritance that, unlike conventional pathogens, lack agent-specific nucleic acid genomes (5, 6). Prions have been described in both mammals (e.g., bovine spongiform encephalopathy and Creutzfeldt–Jakob disease) and fungi ([URE3], [PSI], and [Het-s]). Replication of prions requires a self-propagating modification of an otherwise non-prion host protein. Usually the mechanism involves the recruitment of the normal form of the protein into a growing amyloid-like prion aggregate. In many cases the presence of prions is a disease state, but some prions play normal physiological roles (7). Although amyloid-like protein aggregation is typical of many important protein misfolding diseases, including Alzheimer’s disease and type 2 diabetes, most of these diseases are not known to be naturally transmissible or heritable because of transfer of the amyloid. However, experimental inoculations of amyloid preparations can enhance amyloidosis in nai¨ve mice that are strongly primed for the development of amyloidosis (8, 9). This suggests that there is potential for amyloidoses, in general, and AA amyloidosis specifically, to be transmissible and, hence, prion-like. For such transmissions to be significant in the real world, there must be practical routes of transmission and the potential for inducing disease in natural, rather than artificially primed, hosts. The shedding of AA amyloid into the feces of cheetahs suggests a potential route of transmission (Fig. 1) (4). Although the fecal amyloid can promote amyloidosis on i.v. inoculation into mice, this is only true in mice that were primed for amyloidosis by injections of an inflammatory chemical (silver nitrate) that dramatically boosts serum SAA levels. The silver nitrate treatment alone causes spontaneous amyloidosis in these mice, albeit at a slower pace than when the mice are inoculated with exogenous amyloid. Thus, it remains to be determined whether fecal amyloid can actually initiate, rather than enhance, amyloidosis in either mice or cheetahs and, if so, by what route of inoculation. One possible mode of entry would be oral because AA amyloid can be active in primed mice when administered orally as well as intravenously (9, 10). Another potential route would be direct inoculation of fecal amyloid into the blood stream through cuts or abrasions. It should be noted that Zhang et al. (4) inoculated mice with highly concentrated preparations of fecal amyloid. Hence, it is unknown whether amyloid concentrations in feces would allow transmission to nai¨ve recipients by any peripheral route. If fecal amyloid can be transmitted to other captive cheetahs, what makes these animals so susceptible to AA amyloidosis? The fact that mice can be primed for AA amyloidosis by inflamm tory stimuli raises the possibility that inflammation is also important in cheetahs. Indeed, inflammatory diseases are prominent in captive cheetahs with AA amyloidosis, and a number of precipitating factors, including chronic infections, diet, and stress, have been identified (2, 3). Other possibilities include genetic predispositions of cheetahs to AA amyloidosis because of their SAA sequence or expression level. Interestingly, a gene polymorphism has been identified in captive cheetahs that flanks the SAA1 gene and strongly affects its transcriptional induction in response to inflammation (11). Expression of other proteins can also profoundly enhance susceptibility of animals to AA amyloidosis, as shown by modulation of pentraxin levels in hamsters (12). The genetic homogeneity of captive cheetahs may enhance these susceptibility problems (11, 13), but does not appear to be the sole issue (3). The very factors that might make cheetahs susceptible to exogenous AA amyloid ‘‘infections’’ should also potentiate spontaneous AA amyloidosis in these animals. There is precedent for this in the spontaneous amyloidosis that occurs in silver nitrate-primed mice. By analogy, it remains possible that the high incidence of AA amyloidosis in cheetahs is caused by spontaneous disease exacerbated by the inflammatory stimuli, stresses, and inbreeding of captivity rather than exposure to fecal amyloid. Further studies will be required to resolve these questions. AA amyloidosis susceptibility issues may have serious implications for cheetah conservation efforts. If the objective is to rescue the wild cheetah population by releasing cheetahs bred in captivity, then it will be important to know the impact of releasing amyloidotic animals into the wild. Will AA amyloidosis continue to progress and affect the survival of released cheetahs? Can the disease be spread to wild cheetahs? One encouraging observation is that, relative to captive cheetahs, wild Namibian cheetahs are remarkably free of disease, including inflammatory diseases such as AA amyloidosis and gastritis (3). Perhaps lower chronic levels of inflammation, and hence serum SAA levels, make them less susceptible than captive cheetahs to AA amyloid shed by other animals. Although major questions remain about the etiology of AA amyloidosis in captive cheetahs, it may be wise to take measures to limit exposure of cheetahs to potential sources of amyloid ‘‘infectivity.’’ The demonstration that cheetah AA amyloid is active in mice indicates that there is cross-species promiscuity in its amyloid-inducing capacity. This promiscuity might also work in reverse, rendering cheetahs susceptible to AAamyloid- laden tissues of other species that might be fed to them. Interestingly, foie gras was recently shown to contain AA amyloid that could accelerate amyloidosis when fed to mice (9). Thus, consideration of a variety of potential sources of exposure for cheetahs seems warranted. Furthermore, if chronic inflammation enhances disease susceptibility, then anti-inflammatory therapies may be helpful. Is AA amyloidosis in cheetahs a prion disease? The answer depends on whether AA amyloidosis in captive cheetahs is caused by spontaneous disease or transmission of amyloid between animals. Environmental influences on AA amyloidosis epidemiology could be due to the presence of either ‘‘infectious’’ amyloid, a prion-like etiology, or to factors that enhance the incidence of spontaneous disease, i.e., a non-prion etiology. Even if transfer of AA amyloid between cheetahs enhances AA amyloidosis, the question would remain as to whether the transferred amyloid initiates the disease de novo or merely accelerates ongoing disease. The latter scenario would place AA amyloidosis into a gray area with respect to the basic prion concept. In this instance, prion transmission would affect the kinetics of the disease without actually initiating it. Regardless of prion semantics, there could be practical consequences of such kinetic phenomena in both animals and humans. For instance, recent studies have shown that in ection of -amyloid can enhance Alzheimer’s-like amyloidosis in transgenic mice (14). This raises the possibility that inadvertent transfer of -amyloid from one person to another could accelerate the neurodegenerative process to the point where it becomes Alzheimer’s disease as opposed to normal aging. In this example, as well as in cheetah AA amyloidosis and many other protein misfolding diseases, the basic problem is likely the outpacing of an organism’s protein quality control mechanisms. This may sometimes be more a problem of the rate, rather than of the instigation, of protein misfolding.
Fig. 1. Diagram of AA amyloid formation and the potential prion-like transmission of AA amyloidosis by fecal shedding and oral uptake of the amyloid. The photo shows an example of Congo red-stained AA amyloid fibril deposits in hamster liver tissue (courtesy of John Coe, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases).
ACKNOWLEDGMENTS. This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. 1. Balch WE. Morimoto RI, Dillin A, KellyJW(2008) Adapting proteostasis for disease intervention. Science 319:916–919. 2. Papendick RE, Munson L, O’Brien TD, Johnson KH (1997) Systemic AA amyloidosis in captive cheetahs (Acinonyx jubatus). Vet Pathol 34:549–556. 3. MunsonL, et al. (2005) Extrinsic factors significantly affect patterns of disease in free-ranging and captive cheetah (Acinonyx jubatus) populations. J Wildl Dis 41:542–548. 4. Zhang B, et al. (2008) Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease. Proc Natl Acad Sci USA 105:7263–7268. 5. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383. 6. Wickner RB, et al. (2004) Prion genetics: New rules for a new kind of gene. Annu Rev Genet 38:681–707. 7. Coustou V, Deleu C, Saupe S, Begueret J (1997) The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. Proc Natl Acad Sci USA 94:9773–9778. 8. Kisilevsky R, Boudreau L (1983) Kinetics of amyloid deposition. I. The effects of amyloid-enhancing factor and splenectomy. Lab Invest 48:53–59. 9. Solomon A, et al. (2007) Amyloidogenic potential of foie gras. Proc Natl Acad Sci USA 104:10998–11001. 10. Lundmark K, et al. (2002) Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc Natl Acad Sci USA 99:6979–6984. 11. Zhang B, et al. (March 28, 2008) Characterization of the cheetah serum amyloid A1 gene: Critical role and functional polymorphism of a cis-acting element. J Hered, 10.1093/jhered/esn015. 12. Coe JE, Ross MJ (1990) Amyloidosis and female protein in the Syrian hamster: Concurrent regulation by sex hormones. J Exp Med 171:1257–1267. 13. O’Brien SJ, et al. (1985) Genetic basis for species vulnerability in the cheetah. Science 227:1428 – 1434. 14. Meyer-Luehmann M, et al. (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784. 7114 www.pnas.orgcgidoi10.1073pnas.0803438105 Caughey and Baron
http://www.pnas.org/cgi/reprint/0803438105v1?etoc
Monday, May 12, 2008
Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease
http://betaamyloidcjd.blogspot.com/2008/05/fecal-transmission-of-aa-amyloidosis-in.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/2008/03/10-million-baby-boomers-to-have.html
Original Paper
Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
Laura Debatina, Johannes Strefferb, Markus Geissenc, Jakob Matschkec, Adriano Aguzzia, Markus Glatzela, c
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
Sunday, April 27, 2008 re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease Greetings,
I thought this most important research by Aguzzi et al 'Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease' most important, and thought further reading of this study should be at hand.
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
Draft Factual Account #5
10. On 28 June 1986 Mr Jeffrey examined tissue sections taken from the brain of a nyala which had been kept at Marwell Zoo.(S Jeffrey para 6; YB86/7.8/1.1 ) This examination, and subsequent consideration of the report, are described in the CVL DFA.
51. On 10 June 1987 Mr Bradley sent a BSE update to Dr Watson. It discussed, amongst other things, the nyala case and subsequent paper, the work of Mr Wilesmith, the upcoming BCVA meeting and the work of Dr Kimberlin.(YB 87/6.10/1.1 )
63. On 22 June 1987 Mr Bradley sent a memo to Mr Wells detailing actions taken to date. It noted that publication has been discussed with the CVO and halted and that there were now at least 9 suspect herds and a case in a gemsbok at Marwell.(YB 87/6.22/2.1 )
74. On 1 July 1987, Mr Bradley wrote to Mr Jeffrey to tell him that his article on spongiform encephalopathy in a nyala was not authorised for publication, and that while he made comparisons with scrapie, the CVO was unlikely to give his approval.(YB87/6.29/3.1; YB87/7.1/2.1; YB87/7.1/3.1-3.10 ) This is further discussed in the CVL DFA.
153. On 11 December 1987, Mr Jeffrey's paper on the nyala was submitted for publication in the journal Veterinary Pathology. The paper had first been drafted the paper in autumn 1986. (S 64 Jeffrey para 10) The title of the paper was changed from 'A scrapie-like disorder in a nyala' to 'A spongiform encephalopathy in a nyala.' Other references to scrapie were also amended.( S Jeffrey para 10; S 65 Wells para 55; YB87/11.11/2.1; YB87/11.17/3.1; YB87/11.23/2.1. )
Spongiform encephalopathy in a nyala (Tragelaphus angasi).
Vet Pathol 1988 Sep;25(5):398-9 Jeffrey M, Wells GA Lasswade Veterinary Laboratory, Midlothian.
166. In January 1988, Mr Wilesmith was informed of the June 1987 case of SE in the gemsbok. He discovered from the Winchester VIC that both the >nyala and the gemsbok had received rations containing MBM and this provided further support for his hypothesis.( S Wilesmith para. 37)
Draft Factual Account #4
28. On 28 June 1986 Dr Jeffrey examined tissue sections taken from the brain of a nyala which had been kept at Marwell Zoo. (S Jeffrey para 6; YB86/7.8/1.1 ) The nyala had shown unusual nervous symptoms two weeks prior to being put down on welfare grounds. These symptoms included 'weaving with the head and neck, holding the head on its side and frequent nibbling near the tailbone.'(YB86/6.23/1.1 ) The sections were originally necropsied by Mr Geoff Holmes at the Winchester VIC.(YB86/5.29/1.1; YB86/6.18/1.1 ) The nyala (tragelaphus angasi) is not an antelope but belongs to the same family (species group) as cattle.
29. Dr Jeffrey observed that the brain showed taxonomic lesions of spongiform encephalopathy and that the similarity of the lesions to natural sheep scrapie was striking, and indeed he thought that in comparison to natural sheep scrapie the lesions were particularly florid.(YB86/7.2/1.1; S Jeffrey para 9 ) The sites (neuroanatomical location) and cellular location (grey matter neuropil and neuronal cytoplasmic vacuolation) were distinctive and characteristic of the TSEs. Dr Jeffrey sent a slide of the nyala brain to Dr Richard Kimberlin at the NPU in the latter quarter of 1986 who 'vividly recollect[ed] seeing the results down the microscope because the pathology was so striking'.(YB 98/11.18/1.1 )
30. Following a field visit to Marwell Zoo on 21 July 1986,(YB86/7.24/1.1 ) a report was compiled by Mr Holmes at Winchester VIC and a scientific paper prepared for publication in a journal.(S Jeffrey para 10 ) Dr Jeffrey conferred with Mr Wells, his line manager at the CVL, in the preparation of the paper.(S Jeffrey para 9; S Wells 1st para 55 ) Dr Jeffrey was not sure of the exact date he submitted the paper to the Animal Health and Veterinary Group (AHVG) for publication but said it was some time in Autumn 1986.(S Jeffrey para 10; YB86/11.00/1.1 ) Dr Jeffrey did not form any conclusions about the origins of the disease in this animal, but he discussed the case with the CVL Epidemiology Department, and they agreed to keep a 'watching brief' on the situation.(S Wilesmith para 11)
89. On 17 June 1987 the Annual Report of the CVO for 1986 was published, having been submitted for publication on 1 June 1987.( M24 Tab 2 at 69 ) The Report described the discovery of a 'Scrapie-like disease in a captive nyala' and noted that 'Transmissible spongiform encephalopathies have been reported in man, sheep and goats (scrapie), mule deer and mink.'
91. On 19 June 1987 Mr Bradley sent Dr Watson a BSE Update. Amongst other things it was noted:(YB 87/6.19/3.1-3.2 )
"The final draft Vet Rec paper has been prepared and submitted for authority to publish. This has been rejected by CVO whilst scrapie is mentioned. For this and other reasons the paper is temporarily withdrawn until further information is available"
92. On 19 June 1987 Dr S.H. Done diagnosed spongiform encephalopathy in a gemsbok from Marwell Park.(YB87/6.19/3.2; YB876.8/3.1; YB87/6.10/3.1; YB87/6.25/1.1 ) This was the zoo was from which the SE-infected nyala had come. While the nyala was from the same species group as cattle, the gemsbok is an African antelope.
100. On 1 July 1987 Mr Bradley wrote to Dr Jeffrey to tell him that his article on spongiform encephalopathy in a nyala was not authorised for publication, and that while he made comparisons with scrapie, the CVO was unlikely to give his approval.(YB87/7.1/3.2; YB87/6.29/3.1; YB87/7.1/2.1 ) The initial title of the paper was 'Scrapie-like disorder in a nyala'.( S Jeffrey para 12 ) At the request of Tolworth, the title of the paper was eventually changed to 'Spongiform encephalopathy in a nyala'.( YB87/11.00/1.1 ) Because of the original references to the scrapie-like nature of the disorder the paper was delayed for publication and was not published until September 1988.( J/VP/25/398 ) Dr Jeffrey told the BSE Inquiry that he resisted the move to alter his paper because it 'would have been negligent to try and publish that without a reference to scrapie'.(T25 at 32 )
157. On 17 November 1987 Mr Bradley minuted Dr Jeffrey noting that the title to his nyala paper was likely to be unacceptable to "senior management" for "veterinary political reasons". He also recommended that where comparisons were made with scrapie the emphasis ought to be altered.(YB 87/11.17/1.1 )
433. On 23 October 1989 Dr Watson told Mr Wells that the CVL were to supply material from the kudu and nyala to the NPU for transmission to mice. Dr Watson said this was an important transmission experiment designed to establish the relationship between the disease in zoo animals and cattle.(S Watson 1st para 134 ) Mr Bradley provided Dr Watson with a list of tissues that were to be sent to the NPU on 24 November 1989.(YB89/10.24/4.1 )
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BSE Inquiry site Draft Factual Account 13 extracts related to zoo animals:
19. On 24 January 1990 Mr Bradley sent to Dr Watson a summary of the main points of a meeting held with the Minister the same day.(20) The minute noted: "The Minister played Devil's advocate in relation to: ... 5. MBM exports unethical. All should be labelled & a letter should be sent to all countries to which MBM was exported should be sent." [No such letter was sent.]
28. By 12 February 1990 the nyala and kudu tissues and the placenta had been inoculated into mice at the NPU.(33) After his investigations into the alimentary tract, ... Mr Bradley said in a minute dated 12 February 1990 that:(36) "It is very clear that it is important to initiate studies now in a much wider range of tissues and in multiple specimens than can be accommodated in the annual quota of 30 for the next two years." Mr Bradley attached a table showing the progress of infectivity studies:..fixed nyala brain, fixed kudu brain, buffy coat.
57. On 17 September 1990 Mr Bradley circulated a minute with regards to an offer by Dr Schellekers of the Netherlands to collaborate on attempting to transmit BSE to chimpanzees.(YB90/9.17/1.1) Mr Wells and Dr Rosalind Ridley, who was conducting the marmoset experiment, told Mr Bradley that they did not feel there was any greater justification for an attempted transmission in chimpanzees than marmosets.(S Bradley 3rd para 40 ) Mr Bradley passed on this view to the CVO.(YB90/9.23/1.1; YB90/9.26/3.1 ). [This is ignorant beyond belief.]
67. In Spring 1991 Mr McGill performed a review of 200 brains that had, using the obex histopathological method, been deemed BSE-negative.(110) This diagnostic approach, that had been developed for use within the VIS, used a single section from the medulla to look for spongiform change. In his review Mr McGill examined other parts of the brain.(111) In his statement to the BSE Inquiry Mr McGill said:
Upon closer examination, three of the 200 'BSE-negative' brains proved positive for spongiform changes diagnostic of BSE.(112) This represents an overall diagnostic accuracy of 99.85%, exceeding the 99.6% previously published for the same standard diagnostic technique. Despite this, at the behest of MAFF managers, the emphasis of the study and its provisional title had to be changed, from accurately representing the whole negative 10%, to a study examining this 10% minus any mention whatsoever of BSE-affected cattle going undiagnosed. I therefore had to reluctantly locate and analyse three new BSE-negative suspect brains.(113)
76. In mid-1991 it was decided that a proposed survey of 300 deer brains would proceed.(124) As with the hound survey, there were difficulties in collecting the material in a manner optimal for histopathological examinations.(See YB92/11.4/2.1) During the period 1986 to 1996, 26 deer brains were referred for examination to the Consultant Pathology Unit at the CVL, but none of these showed evidence of an SE.
103. On 16 July 1992 a meeting was held at CVL to discuss the research proposals relating to the studies on SEs in a greater kudu at a zoo. (S Bradley 3rd para 65 ) Three main experiments were proposed: to determine the distribution of agent in tissues; to study the epidemiology; and to strain type isolates from a brain of a new case of spongiform encephalopathy. Formal proposals were later drawn up and Mr Bradley became the Project Officer for the experiments.
108. Mr Bradley and Mr Dawson met staff at London Zoo on 23 March 1993 to discuss tissue selection for the proposed transmission studies on BSE-infected kudu material.(166) The Zoo did not want to keep the kudu, but moving them to the CVL was ruled out because of inadequate facilities to care for them. The investigations into the distribution of the SE agent in various tissues began in June 1993.
121. On 9 October 1993 Mr Wilesmith and others published a paper on the additional cases of TSE in the herd of greater kudu at London Zoo.(S Wilesmith 2nd para 95 ) On the basis of feeding histories, the authors concluded that horizontal transmission had occurred. However, subsequent investigations based at the zoo revealed that the affected animals were most likely to have been infected from the feedborne source.
143. On 3 July 1994 Mr Bradley was informed that two more kudu were to be culled.( Bradley 3rd para 86 ) He visited the London Zoo on 21 July 1994 to review the progress of the studies on TSEs in zoo animals. Necropsies were to be carried out on the kudu and tissues collected for further transmission studies. At this stage the mice that had been inoculated with kudu tissues in August and September 1993 had not succumbed to spongiform encephalopathy. The Zoo authorities wanted to move the kudu because of the possibility of bad publicity.(YB95/2.10/1.6) This was discussed at a SEAC meeting on 2 February 1995. The meeting agreed that the risk to Zoo visitors was minuscule or non-existent. Mr Bradley's case control study indicated that infected feed was the most probable cause of the BAB kudu SE cases.
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46. On 28 June 1990 Mr Bradley informed Mr Wells that a survey of hounds was to commence.(68) The hound survey arose because the Tyrrell Committee had recognised that domestic pets might prove susceptible to the unconventional agent of BSE and recommended monitoring the health of animals fed offal, carcases or meat and bone meal.(M11a Tab 8 )
47. A total of 444 hound brains of mixed breeds from 101 kennels across the United Kingdom were collected and examined. Histopathological changes consistent with a florid spongiform encephalopathy similar to that reported in cats was not observed. However, the report of the survey identified serious flaws in the survey's design. Mr Wells said in a minute to Mr Bradley in October 1991 that 'the survey as designed has little to offer scientifically'.(YB91/10.17/1.1)
54. On 20 August 1990 Mr Wells confirmed the parenteral transmission of BSE to a pig.(YB90/7.20/2.1) The pig was inoculated in February/March of 1989 and was slaughtered in July 1990.(S Wells 2nd para 40) An interim report was prepared for SEAC(84) and a press conference was held on 24 September 1990 to announce the parenteral transmission of BSE to pigs.(85) The transmission of BSE to pigs was a major factor in the ban on SBOs being extended to all animal feed. Experiments were also conducted by orally dosing pigs with BSE infected material but when the pigs were killed after seven years they were not found to be incubating the disease.(S Wells 2nd para 40 )
55. By August 1990 a total of 10 cases of FSE in domestic cats had been confirmed.(S Wilesmith 2nd para 109 ) Mr Wilesmith designed a questionnaire to be completed by the veterinarians who clinically identified FSE for the purposes of an epidemiological investigation. In addition to this investigation, the University of Bristol was subsequently granted a MAFF contract for a study in collaboration with the NPU to ascertain whether the condition in cats was transmissible to mice and, if so, to undertake strain typing of the agent.(S Wells 2nd para 104; YB 92/6.19/5.1 ) Mr Wells was appointed Project Officer to monitor the study. When the study was completed it showed that the disease in cats was transmissible and that similarities in the biological characteristics of FSE and BSE on transmission to mice indicated that the two diseases probably arose from a common source.(J/VR/134/449 )
64. In February 1991 Mr Mark Robinson began studies on the transmission of BSE to mink.(S Wilesmith 2nd paras 117-118 ) This study was done in collaboration with the United States Department of Agriculture (USDA), the Agricultural Research Service (ARS), and the Department of Veterinary Science at the University of Wisconsin, USA. The results of this study were discussed at the 10th CVL/NPU BSE R&D meeting held on 27 April 1993.(YB93/4.27/1.1) The results indicated that mink were susceptible to BSE, and in contrast to previous attempts to transmit scrapie to the species, were susceptible by the oral route of challenge.(J/JVIR /75/2151)
99. On 11 April 1992 Mr Bradley prepared a paper for the Lamming Expert Committee on Animal Feedingstuffs.(153) Some of the areas covered in the paper were tallow, the danger of BSE to pigs, the effect of the species barrier, tissue infectivity of lambs and calves, scrapie incidence and the danger of dogs developing SEs.
116. In July 1993 studies involving the oral exposure of pigs to scrapie were started the CVL.(179) Such studies were recommended by the expert committee on feedingstuffs chaired by Professor Lamming, because it was found that pigs had been orally exposed not only to BSE but also to scrapie. The pigs were orally exposed to scrapie-infected brain material in November 1993 and while the experiment remains in progress, no pigs have been shown to have developed the disease to date.
123. In December 1993 Dr Ken Charlton of the Animal Disease Research Institute, Nepean, Ontario, Canada, visited the CVL bringing material from a suspect case of BSE in Canada. The CVL confirmed that the case was a BSE case and reported it to the Canadian authorities.(189) in 1994.
152. On 13-16 February 1995 ... ...BSE to pigs - Further work to clarify the finding of non-specific vacuolation in the brains of control pigs was needed.
...BSE to chickens - Sub-passage in chickens and mice of various tissues from experimentally infected birds was needed to clarify the findings of neurological signs without neuropathology in inoculated birds.
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Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
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