Saturday, February 16, 2013

Prions, prionoids and pathogenic proteins in Alzheimer disease

transmission or seed ???

iatrogenic ???

what if ???

Prion 7:1, 55–59; January/February 2013; © 2013 Landes Bioscience MINI-rev iew Mini-REVIEW

Prions, prionoids and pathogenic proteins in Alzheimer disease

Karen H. Ashe1,2,3,* and Adriano Aguzzi4

*Correspondence to: Karen H. Ashe; Email: Submitted: 10/18/2012; Revised: 11/14/2012; Accepted: 11/29/2012

1Department of Neurology; N. Bud Grossman Center for Memory Research and Care; University of Minnesota; Minneapolis, MN USA; 2Department of Neuroscience; N. Bud Grossman Center for Memory Research and Care; University of Minnesota; Minneapolis, MN USA; 3GRECC; VA Medical Center; Minneapolis, MN USA; 4Institute of Neuropathology; University Hospital Zurich; Zurich, Switzerland Keywords: prions, prionoids, PrP, amyloid-β, tau, pathogenic proteins, Alzheimer disease

Like patients with prion disease, Alzheimer patients suffer from a fatal, progressive form of dementia. There is growing evidence that amyloid-β (Aβ) aggregates may be transmissible similar to prions, at least under extreme experimental conditions. However, unlike mice infected with prion protein (PrP) prions, those inoculated with Aβ do not die. The transmission of Aβ and PrP thus differs conspicuously in the neurological effects they induce in their hosts, the difference being no less than a matter of life and death. Far from being a mere academic nuance, this distinction between Aβ and PrP begs the crucial questions of what, exactly, controls prion toxicity and how prion toxicity relates to prion infectivity.

Prions in Neurological Disease

Stanley Prusiner introduced prions in 1982 as the self-replicating forms of the prion protein that accumulate in certain transmissible diseases of the central nervous system, such as scrapie and Creutzfeldt-Jakob disease.1 Although prions represent novel infectious agents lacking pathogen-encoded nucleic acids, their discovery relied upon a century-old paradigm, formalized into postulates by Robert Koch, for identifying pathological microbial agents. A key concept in Koch’s postulates is that the microbe responsible for a given disease must cause that same disease when inoculated into a susceptible host. In prion disease, the afflicted individual suffers from a progressive deterioration in neurological function that culminates, inevitably, in death. By systematically sifting through brain extracts from scrapie-infected hamsters, Prusiner found that the deadliest inoculates contained fibrillar aggregates of a proteolytic fragment of the prion protein, PrP27- 30. We now know that this fragment is derived from the scrapie isoform of the prion protein, PrPSc, an aggregated, alternatively folded conformer of the cellular prion protein, PrPC.2

In 2000, Lary Walker first demonstrated that intra-cerebral inoculations of brain extracts from amyloid plaque-containing brain tissue from Alzheimer patients accelerate amyloid plaque deposition and β-amyloidosis in transgenic mice expressing human Aβ proteins.3 The acceleration of β-amyloidosis by inoculates containing Aβ fibrils, which form amyloid plaques, has been replicated in at least four other laboratories using inoculates from humans, several lines of plaque-forming transgenic mice and, most recently, fibrillar synthetic Aβ aggregates and synthetic Aβ dimers.4-7

While these results indicate that fibrillar conformers of Aβ proteins can self-replicate in susceptible hosts, it is still unclear whether such replication can be maintained over multiple serial passages from one animal to another. The latter is an integral part of the definition of a “prion.” For the sake of the following discussion, we will refer to PrPSc as the aggregated form of PrPC found in transmissible spongiform encephalopathies (TSEs), and to “prions” as the infectious agent of TSEs as measured with microbiological methods. In this frame of reference, prions are composed of PrPSc, but not all PrPSc is necessarily infectious.8

Infectious Agents, Prions and Prionoids

In 1966 Carlton Gajdusek astonished the scientific world with the claim that the fatal degenerative disease kuru was transmitted through ritualistic cannibalism among the Fore peoples of New Guinea;9 the proposal that the elusive infectious agent in kuru was a prion was no less surprising. Now, however, the radical properties ascribed to prions threaten to undermine the original meaning of “infectious agent.” In the following discussion, an infectious agent transmits a disease causing deficits in the host that are the same as those in the donor and share the same pathophysiology. Simply put, infectious agents are the biological basis of ill health that can be passed between living beings.

Prions fulfill the above definition since they were initially discovered as true infectious agents using microbiological methods. However, many other proteins can aggregate into geometrically arranged structures that can seed—in vitro and in vivo—compartments containing the parent protein in a monomeric soluble state.

Simply equating the capability of seeding with the term “prion” is an oversimplification. Any inorganic crystal can seed a supersaturated solution of its cognate salt, whereas bona fide prions have caused epidemics in sheep, cows, mink, felines and humans (kuru, as well as iatrogenic and “variant” Creutzfeldt- Jakob disease). Because of their flagrant infectious traits—communicability and contagiousness—the agents of these diseases were not recognized as prions for many decades, and many preeminent scientists deemed them to be “slow viruses.”

Since none of the newly discovered seeded aggregates have yet been shown to be infectious (i.e., communicable or contagious) under natural conditions, we deem it prudent to refer to them as “prionoids.”10,11 Maintaining a distinction between prions and prionoids implies the existence of underlying biological processes that govern the natural transmission of diseases between organisms, including the sophisticated mechanisms by which extraneural inoculations of prions subvert the immune system to reach and damage the brain (reviewed by Aguzzi and Calella12).

Fortunately, there is no indication that such processes exist for Aβ prionoids. However, the demonstration of inter-individual transmissibility would warrant upgrading the status of such agents to bona fide prions, as seems very likely to occur in the case of AA amyloid.13


With the exception of PrPSc, there is no experimental evidence that the prions or prionoids in neurodegenerative diseases are the pathogenic proteins [star (*) proteins] inducing the neurological deterioration that devastates patients. For a hundred years, neurofibrillary tangles—the intracellular amyloid inclusions that form when tau takes on novel β-sheet structure—were believed to induce neuron death and impair cognition. However, in 2005 this hundred-year-old hypothesis was disproven when it was shown that reducing soluble tau in a neurodegenerative mouse model with neurofibrillary tangles led to the cessation of neuron loss and the improvement of memory function, in spite of the startling observation that the neurofibrillary tangles kept accumulating, reminiscent of prionoids.14 The negative case for β-amyloid plaques containing *proteins stems from multiple lines of evidence, including the failure of Alzheimer patients to improve following Aβ immunotherapy that nonetheless successfully removed amyloid plaques,15 and the ability of immunotherapy to reverse deficits in mice without changing plaque load.16,17 Compared with the proteins comprising amyloid lesions, prions, and prionoids, relatively little is known about *proteins and their mechanisms of action.


The conclusion that the removal of the inclusions would not cure familial ataxia type 1 prompted Harry Orr and Huda Zoghbi to search for the pathogenic form of PolyQ/ataxin-1 causing the neurological abnormalities in the disorder. Discovering the mechanism by which PolyQ/ataxin-1 damages neurons emerged from understanding the normal physiological roles of ataxin-1, which is a nuclear protein. The pathogenic form of PolyQ/ataxin-1 is not a misfolded form of ataxin-1; it contains no novel secondary structures, no β-sheets that are not normally present in the brain. Its pathological effects arise from alterations in its binding affinities with its normal nuclear partners, the transcriptional regulator Capicua and the regulator of RNA splicing RMB17,22 leading to changes in the transcriptome that, presumably, affect neuronal function and viability. Thus, the pathogenic form of PolyQ/ataxin-1 is not a prionoid; it is neither a misfolded protein nor a soluble aggregate of the parent protein.

_This may prove to be a profoundly important lesson for the entire field of neurodegenerative disease research._


A Puzzle and Two Hypotheses Both patients with prion disease and Alzheimer disease suffer from fatal, progressive forms of dementia. However, while mice infected with PrP prions die, those inoculated with Aβ prions do not. Only two hypotheses can explain the stark contrast between the fatality rates caused by PrP and Aβ inoculations in mice. • Hypothesis 1: all aggregated proteins (prions and prionoids) are bad. Aggregates are pathogenic, but different aggregates exert their effects on different cellular pathways. For example, the pathogenic pathway for Aβ aggregates in humans, distinct from that of PrP prions, may not exist in mice. • Hypothesis 2: not all aggregates are bad. Aggregates are not invariably pathogenic; rather, variants of parent proteins (*proteins) cause the cellular dysfunction that leads to a neurological illness (Fig. 1). These pathogenic variants need not be misfolded or aggregated forms of the parent proteins. Recent advances in our understanding of the neurotoxicity of PrP and Aβ favor hypothesis 2, as discussed below.


Figure 1. Prions, prionoids and pathogenic proteins in neurodegenerative diseases. PrPSc is considered to be the transmissible agent of the prion causing scrapie, Creutzfeldt-Jakob disease and related spongiform encephalopathies. Nucleating fibrillar protein aggregates (“prionoids”) are found in many neurodegenerative diseases. With the exception of PrPSc, there is little evidence in mice or humans linking prionoids in the brain to the pathophysiological processes that cause the disorders connected with these proteins. Instead, accumulating data indicate that the brain dysfunction and neurological signs associated with these illnesses are caused by non-fibrillar variants of the parent proteins (*proteins). In the case of Aβ, brain dysfunction in mice and CSF tau abnormalities in humans are strongly associated with a soluble 56-kDa assembly, Aβ*. The existence of other Aβ* molecules has not been excluded. The *proteins need not be misfolded in the sense of adopting novel secondary structure, which invariably involves β-sheets. PolyQ/ataxin-1 is the best example. Distinguishing between prionoids and *proteins, and understanding how *proteins cause neurological illness, will advance our progress in treating these profoundly devastating and fatal disorders.


There has been recurrent discussion as to whether the self-replicating material in prion disease (the “prion”) is physically identical with the neurotoxic entity. In this context, John Collinge has recently proposed the term “PrPL” to denote a hypothetical moiety that may be neurotoxic yet differs from PrPSc.24 However, the idea that PrP may produce neurological disease without the generation of infectivity dates back to 1990 when transgenic mice that spontaneously developed prion disease were created. These mice expressed PrP carrying a mutation linked to a familial prion disease, developed ataxia, lethargy and rigidity, and invariably died, but their brains contained few or no infectious prions, suggesting that “an inborn error of PrP metabolism could produce neurologic disease without the generation of infectivity.” 25 It is possible, and indeed very likely in our view, that PrPSc and the various non-infectious neurotoxic variants of PrP, which include PrP with supernumerary octapeptide repeats26 and PrP versions with interstitial deletions of the “hinge” region between the unstructured N-terminus and the globular domain,27 activate neurotoxic pathways converging with those triggered by prion infection (Fig. 2).


In the absence of animal models, harboring Alzheimer-related mutations exclusively, that exhibit the full spectrum of disease, beginning with subtle neuronal dysfunction and culminating with fatal cognitive devastation, the question of whether asymptomatic β-amyloidosis requires Aβ*56 to develop into full-blown Alzheimer disease cannot be addressed experimentally. It is possible that one or more non-prionoid form of Aβ triggers neuronal dysfunction and neurodegeneration in Alzheimer disease. Discovering these pathogenic forms will depend upon the creation of high fidelity model systems of Alzheimer disease.


In bona fide prion diseases, a very large body of evidence links the aggregated form of PrP, PrPSc, to both prion infectivity and prion neurotoxicity. However, non-infectious, yet neurotoxic, variants of PrP occur naturally and more such variants have been constructed experimentally, indicating that the phenotypic expression typical of prion diseases can be triggered by events occurring downstream of prion infection. There is little evidence in mice or humans linking the neurological effects of Aβ to the nucleating forms of this protein, while emerging data point to a specific non-nucleating form of Aβ, Aβ*56, that produces some of the neurological signs of disease. However, Aβ*56 is not sufficient to induce the inexorable neurological deterioration that characterizes Alzheimer disease, indicating that other critical factors or forms of Aβ work in collaboration with Aβ*56 to destroy the brain. Curing prion and Alzheimer disease will depend upon developing a deeper understanding of the pathogenic forms of PrP and Aβ that cause the brain dysfunction underlying these deadly illnesses.

Ann N Y Acad Sci. 1982;396:131-43.

Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob disease).

Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC.


Ample justification exists on clinical, pathologic, and biologic grounds for considering a similar pathogenesis for AD and the spongiform virus encephalopathies. However, the crux of the comparison rests squarely on results of attempts to transmit AD to experimental animals, and these results have not as yet validated a common etiology. Investigations of the biologic similarities between AD and the spongiform virus encephalopathies proceed in several laboratories, and our own observation of inoculated animals will be continued in the hope that incubation periods for AD may be even longer than those of CJD.

CJD1/9 0185 Ref: 1M51A


Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray


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 neurodegenerative disorders;

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

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

BSE101/1 0136


5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992


1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognized 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 emphasizes the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible. What are the implications for public health?

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

92/11.4/1-1 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 in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.

JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 121/YdeS 92/11.4/1.2

BSE101/1 0136



From: Dr J S Metters DCMO

4 November 1992


CJD1/9 0185

Ref: 1M51A


From: Dr. A Wight Date: 5 January 1993


Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray


Tuesday, October 4, 2011

Molecular Psychiatry

advance online publication 4 October 2011; doi: 10.1038/mp.2011.120

De novo induction of amyloid-ß deposition in vivo

Our results suggest that some of the typical brain abnormalities associated with AD can be induced by a prion-like mechanism of disease transmission through propagation of protein misfolding. These findings may have broad implications for understanding the molecular mechanisms responsible for the initiation of AD, and may contribute to the development of new strategies for disease prevention and intervention.

Keywords: amyloid; prion; protein misfolding; disease transmission

Wednesday, January 5, 2011


David W. Colby1,* and Stanley B. Prusiner1,2


Evaluation of Potential Infectivity of Alzheimer and Parkinson Disease Proteins in Recipients of Cadaver-Derived Human Growth Hormone

David J. Irwin, MD; Joseph Y. Abrams, MPH; Lawrence B. Schonberger, MD, MPH; Ellen Werber Leschek, MD; James L. Mills, MD, MS; Virginia M.-Y. Lee, PhD, MBA; John Q. Trojanowski, MD, PhD JAMA Neurol. 2013;():1-7. doi:10.1001/jamaneurol.2013.1933.

Published online February 4, 2013

Importance Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)–associated proteins (NDAPs) (ie, tau, Aβ, and α-synuclein) suggests possible similarities to the infectious prion protein (PrPsc) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission of NDAPs associated with Alzheimer disease (AD) and other non-PrPsc ND.

Objective To examine evidence for human-to-human transmission of AD, Parkinson disease (PD), and related NDAPs in cadaveric human growth hormone (c-hGH) recipients.

Design We conducted a detailed immunohistochemical analysis of pathological NDAPs other than PrPsc in human pituitary glands. We also searched for ND in recipients of pituitary-derived c-hGH by reviewing the National Hormone and Pituitary Program (NHPP) cohort database and medical literature.

Setting University-based academic center and agencies of the US Department of Health and Human Services.

Participants Thirty-four routine autopsy subjects (10 non-ND controls and 24 patients with ND) and a US cohort of c-hGH recipients in the NHPP.

Main Outcome Measures Detectable NDAPs in human pituitary sections and death certificate reports of non-PrPsc ND in the NHPP database.

Results We found mild amounts of pathological tau, Aβ, and α-synuclein deposits in the adeno/neurohypophysis of patients with ND and control patients. No cases of AD or PD were identified, and 3 deaths attributed to amyotrophic lateral sclerosis (ALS) were found among US NHPP c-hGH recipients, including 2 of the 796 decedents in the originally confirmed NHPP c-hGH cohort database.

Conclusions and Relevance Despite the likely frequent exposure of c-hGH recipients to NDAPs, and their markedly elevated risk of PrPsc-related disease, this population of NHPP c-hGH recipients does not appear to be at increased risk of AD or PD. We discovered 3 ALS cases of unclear significance among US c-hGH recipients despite the absence of pathological deposits of ALS-associated proteins (TDP-43, FUS, and ubiquilin) in human pituitary glands. In this unique in vivo model of human-to-human transmission, we found no evidence to support concerns that NDAPs underlying AD and PD transmit disease in humans despite evidence of their cell-to-cell transmission in model systems of these disorders. Further monitoring is required to confirm these conclusions.

"By interrogating an existing database with information on a cohort of well-characterized patients, we were able to determine that there is no evidence suggesting the pathology of Alzheimer's or Parkinson's can transmit between humans," said senior author John Q. Trojanowski, MD, PhD, professor of Pathology and Laboratory Medicine and co-director of the Penn Center for Neurodegenerative Disease Research." ...

really ???

From: Terry S. Singeltary Sr.

Sent: Tuesday, February 05, 2013 10:56 AM

To: ;

Cc: ; ; VMYLEE@MAIL.MED.UPENN.EDU ; ; ; ; ; ; ; ; ; ;

Subject: Penn study confirms no transmission of Alzheimer's proteins between humans ?

Penn study confirms no transmission of Alzheimer's proteins between humans ?

Contact: Kim Menard 215-662-6183 University of Pennsylvania School of Medicine

Penn study confirms no transmission of Alzheimer's proteins between humans

PHILADELPHIA - Mounting evidence demonstrates that the pathological proteins linked to the onset and progression of neurodegenerative disorders are capable of spreading from cell-to-cell within the brains of affected individuals and thereby "spread" disease from one interconnected brain region to another. A new study found no evidence to support concerns that these abnormal disease proteins are "infectious" or transmitted from animals to humans or from one person to another. The study by researchers from the Perelman School of Medicine at the University of Pennsylvania, in conjunction with experts from the U.S. Centers for Disease Control and the Department of Health and Human Services, appears online in JAMA Neurology.

Cell-to-cell transmission is a potentially common pathway for disease spreading and progression in diseases like Alzheimer's (AD) and Parkinson's (PD) disease as well as frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and other related disorders. It appears that misfolded proteins spread from one cell to another and that the affected neurons become dysfunctional, while these toxic proteins go on to damage other regions of the brain over time.

"By interrogating an existing database with information on a cohort of well-characterized patients, we were able to determine that there is no evidence suggesting the pathology of Alzheimer's or Parkinson's can transmit between humans," said senior author John Q. Trojanowski, MD, PhD, professor of Pathology and Laboratory Medicine and co-director of the Penn Center for Neurodegenerative Disease Research. "We can now redouble efforts to find treatments, via immunotherapies or other approaches to stop the spreading of these toxic proteins between cells."

In order to verify whether such proteins could potentially be carried from person to person, the team of researchers analyzed data from an existing cohort of patients who had received human growth hormone (hGH) from cadaveric pituitary glands via a national program, as a beneficial treatment for stunted growth, before synthetic hGH was available. Nearly 7,700 patients were treated with cadaver-derived hGH (c-hGH) in the US between 1963 and 1985. In the mid-1980s, more than 200 patients worldwide who had received c-hGH inadvertently contaminated with prion proteins from affected donor pituitary tissue went on to develop an acquired form of Creutzfeldt-Jakob disease (CJD), a rare, degenerative, invariably fatal brain disorder caused by pathological prion proteins that also are the cause of Mad Cow disease. Since then, the cohort has been followed to track any additional cases of CJD, with extensive medical histories for patients over the 30+ years since the c-hGH therapy was stopped after the link to CJD was discovered in 1985.

In this current study, researchers looked for signs of an elevated risk of AD, PD, FTLD or ALS among this group and found that none of the c-hGH recipients developed AD, PD or FTLD. The team did identify three ALS cases of unclear significance, given that no traces of ALS disease proteins (TDP-43, FUS and Ubiquilin) were found in human pituitary glands, despite the presence of pathological AD (tau, Aβ) and PD (alpha-synuclein) proteins. This clarified that c-hGH recipients were most likely exposed to these neurodegenerative disease proteins linked to AD, PD and FTLD but this did not result in transmission of disease from person to person.

"This cohort is an invaluable resource and should continue to be followed, especially as we rapidly increase our understanding of disease progression in neurodegenerative conditions," said David Irwin, MD, lead author, and fellow in the Center for Neurodegenerative Disease Research and the department of Neurology in the Perelman School of Medicine.


The other co-authors of this study are Joseph Y. Abrams, Lawrence B. Schonberger, Ellen W. Leschek, James L. Mills, and Virginia M.-Y. Lee. This research was supported by grants from the National Institute on Aging (P30 AG010124, Alzheimer's Core Center grant, T32-AG000255), Intramural Research Program and National Institute of Child Health and Development at the National Institutes of Health.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital – the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

Penn study confirms no transmission of Alzheimer's proteins between humans ?

confused ???

Greetings Jama, Penn state, Perelman School of Medicine Deans et al, eurekalert, Authors et al,

In my opinion, this subject title (NOT a transmission study, but only a study a team of researchers did by analyzed data from hGH recipients years, decades ago), and it’s interpretations, as described by Kim Menard

“Penn study confirms no transmission of Alzheimer's proteins between humans” ,

IN my opinion, is false.

In my opinion, this study does not prove or confirm that Alzheimer’s does not transmit to humans. your title is very misleading in my opinion. very confusing, as the title here stipulated from eurekalert. Penn state DID NOT confirm or prove that Alzheimer’s proteins are NOT transmissible between humans, of the contrary, there is indeed science showing that Alzheimer’s disease IS transmissible. I am very close to all this, please see ;

Penn Study: Transmission of Tangles in Alzheimer's Mice Provides More Authentic Model of Tau Pathology

January 16, 2013


The study demonstrates that synthetic tau fibrils alone are capable of inducing authentic NFT-like tau clumps and initiating spreading of tau pathology in an Alzheimer’s mouse model.

Transmission of Tangles in Alzheimer's Mice Provides More Authentic Model of Tau Pathology, Penn Study Shows

New Model Provides First Step in Generating New Therapies

Friday, February 15, 2013

Scottish TSE Network November Symposium Announcement Event: 12 November 2012 Title: Is Alzheimer’s Disease a transmissible disease? SUMMARY

Cell to cell spread of misfolded protein

A meeting was held on the 12th November hosted by the Scottish Transmissible Spongiform Encephalopathy Network (STN) at the Roslin Institute, University of Edinburgh with the aim of examining whether Alzheimer's disease should be classed as a “transmissible disease”? Speakers included international experts in prion and Alzheimer's diseases examining the evidence from studies in the human population and in animal models. The presentations reviewed the current position and the final discussion drew some important conclusions.

It is well known that in prion diseases an abnormal misfolded protein (PrPSc) derived from a normal host protein (PrPC) accumulates and spreads through the brain along defined neuroanatomical pathways. Prion diseases affect both animals (scrapie in sheep, BSE in cattle, chronic wasting disease in deer) and humans (Creutzfeldt - Jakob Disease (CJD)). Transmission between individuals in the natural state has been observed for some prion diseases, for example in sheep and deer. Many, although not all, prion diseases in animals can be experimentally transmitted from animal to animal, and one has transmitted from animal to human,BSE. CJD can also be transmitted to experimental animals. However, transmission of CJD between humans only occurs very rarely and in exceptional circumstances such as the transfer of tissue from an individual with CJD to another by a surgical procedure or via certain medical treatments. Transmission between individuals and spread from cell to cell within an individual, have both been termed “prion transmission”.

It has been shown in neuropathological studies of brains from patients with Alzheimer’s disease that the pathology also spreads in a predictable way through the brain. This spread of pathology in the grey matter of the brain involves the formation of amyloid plaques, comprised of A, outside nerve cells, and neurofibrillary tangles inside nerve cells. Mice carrying human genes that lead to the deposition of the A peptide in the brain have been used to study aspects of Alzheimer’s disease pathology. Experimental studies show that injection of A plaque material, isolated from a human Alzheimer’s disease brain, or another mouse with A plaques can accelerate the deposition of A in the brain and its deposition along neuronal pathways. This predictable spread from cell to cell has been referred to as “prion-like transmission” and has now been demonstrated not only in mouse models with the A protein, but also in other models of neurodegenerative disease that involve the misfolding of proteins. It was suggested by several of the speakers that the injected misfolded peptide or protein acts as a “seed” for further deposition of misfolded protein akin to the growth of a crystal. It is likely that there are considerable parallels between prion diseases and Alzheimer’s disease in the molecular and cellular events leading to cell to cell transmission.

There is no evidence to date from analysis of patient populations that transmission of Alzheimer’s disease between individuals has occurred. It was concluded that human to human transmission of any protein misfolding disease requires a set of very unusual circumstances to occur, as has been documented in the prion diseases. The evidence from human and animal studies does not support the idea that Alzheimer's disease is transmissible between individuals. The term “prion-like transmission” has been unhelpful in the context of Alzheimer’s disease and other protein misfolding diseases as it does not distinguish between spread between cells and transmission between individuals. The meeting concluded that the term “prion-like cell to cell spread” should be used to convey a clear message. The robust experimental models in prion disease provide an opportunity to understand the cellular and molecular mechanisms of cell to cell spread and identify therapeutic targets to delay disease progression for both prion and Alzheimer’s disease.

Professor Jean Manson, The Roslin Institute, University of Edinburgh and R(D)SVS Easter Bush Professor Hugh Perry, University of Southampton


UPDATE JUNE 28, 2012

Scottish TSE Network November Symposium Announcement Event: 12 November 2012

Chair: Prof Hugh Perry, University of Southampton, Southampton UK

Location: The Roslin Institute Building Auditorium

If you would like to book a place at this event, please let Gila Holliman know.

Cost: £125.

Title: Is Alzheimer’s Disease a transmissible disease?


Session 1:

Prof Bob Will, National CJD Surveillance Unit, Edinburgh UK

Prof James Ironside, National CJD Surveillance Unit, Edinburgh UK

Prof Lary Walker, Emory School of Medicine, Atlanta USA

Session 2:

Prof Mathias Jucker, Hertie Institute for Clinical Brain Research, Stuttgart Germany

Prof William Van Nostrand, Stony Brook University, Stony Brook USA

Dr Claudio Soto, University of Texas Medical School, Houston USA

Session 3:

Dr Fabrizio Tagliavini, Instituto Neurologico Carlo Besta, Milan Italy

Prof Pedro Piccardo, Food and Drug Administration, Washington DC USA

Dr Bruce Chesebro, National Institutes of Health, Missoula USA

Friday, February 15, 2013

Scottish TSE Network November Symposium Announcement Event: 12 November 2012 Title: Is Alzheimer’s Disease a transmissible disease? SUMMARY

Sunday, February 10, 2013

Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?

Sunday, December 9, 2012

Prions, prionoids and pathogenic proteins in Alzheimer disease

Transmission of Prions and Alzheimer’s disease Abeta Amyloid

Claudio Soto, PhD

Mitchell Center for Alzheimer’s disease and Related Brain Disorders, Dept of Neurology

University of Texas Medical School at Houston

Tuesday, October 4, 2011

Molecular Psychiatry

advance online publication 4 October 2011; doi: 10.1038/mp.2011.120

De novo induction of amyloid-ß deposition in vivo

Our results suggest that some of the typical brain abnormalities associated with AD can be induced by a prion-like mechanism of disease transmission through propagation of protein misfolding. These findings may have broad implications for understanding the molecular mechanisms responsible for the initiation of AD, and may contribute to the development of new strategies for disease prevention and intervention. Keywords: amyloid; prion; protein misfolding; disease transmission

see more here ;

Wednesday, March 28, 2012


*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.

Monday, September 26, 2011

Variably Protease-Sensitive Prionopathy, Prionpathy, Prionopathy, FFI, GSS, gCJD, hvCJD, sCJD, TSE, PRION, update 2011


please note, the term prionpathy was first used, then changed to prionopathy for this type prion disease.

this is not the first time the prion names have changed i.e. nvCJD changed to vCJD. ...tss

PSPr: Protease-sensitive prionpathy (Gambetti et al, Ann Neurol 2008; 63:697-708)

American Association of Neuropathologists, Inc.: Abstracts o ... › Home › May 2009 - Volume 68 - Issue 5

American Association of Neuropathologists, Inc.: Abstracts of the 85th Annual Meeting June 11-14, 2009 San Antonio, Texas

As sporadic Creutzfeldt-Jakob disease (CJD), this novel prion disease, named "Protease-Sensitive Prionpathy (PSPr)", includes at least three subtypes ... end

Saturday, August 14, 2010

BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY

Thursday, August 12, 2010

Seven main threats for the future linked to prions

Original Article

A novel human disease with abnormal prion protein sensitive to protease

Article first published online: 20 JUN 2008

DOI: 10.1002/ana.21420

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?


Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.


Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.


I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.


There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.


Wednesday, May 16, 2012

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

Proposal ID: 29403

Friday, September 3, 2010

Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE

Wednesday, September 21, 2011

PrioNet Canada researchers in Vancouver confirm prion-like properties in Amyotrophic Lateral Sclerosis (ALS)


... a TSE is found that is linked to Alzheimer’s disease.

Saturday, February 16, 2013

What’s to like about the prion-like hypothesis for the spreading of aggregated α-synuclein in Parkinson disease?

Thursday, January 17, 2013

TSE guidance, surgical, dental, blood risk factors, Part 4 Infection control of CJD, vCJD and other human prion diseases in healthcare and community settings (updated January 2013)

The Center For Consumer Freedom

Posted On December 20, 2003


Mad Cow Scaremongers


Like many activists, Singletary ignores overwhelming epidemiological and laboratory evidence that rules out a connection between sporadic CJD and beef. Relying entirely on shallow circumstantial evidence and frequent repetition of claims which have been publicly refuted as false, he also blindly insists upon a mad-cow with Alzheimer’s, Parkinson’s, and Lou Gehrig’s disease. His specific allegations have been clearly refuted by Centers for Disease Countrol and Prevention scientists in the journal Neurology.


who are these people ‘The Center For Consumer Freedom’ ?

see full comment on TSS ;

Sunday, September 25, 2011

Mad Cow Scaremongers

Mad Cow Scaremongers by Terry S. Singeltary Sr. a review of the TSE prion agent 2003-2011

Monday, October 10, 2011

EFSA Journal 2011 The European Response to BSE: A Success Story


EFSA and the European Centre for Disease Prevention and Control (ECDC) recently delivered a scientific opinion on any possible epidemiological or molecular association between TSEs in animals and humans (EFSA Panel on Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical BSE prions as the only TSE agents demonstrated to be zoonotic so far but the possibility that a small proportion of human cases so far classified as "sporadic" CJD are of zoonotic origin could not be excluded. Moreover, transmission experiments to non-human primates suggest that some TSE agents in addition to Classical BSE prions in cattle (namely L-type Atypical BSE, Classical BSE in sheep, transmissible mink encephalopathy (TME) and chronic wasting disease (CWD) agents) might have zoonotic potential.


Thursday, August 12, 2010

Seven main threats for the future linked to prions

First threat

The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.

***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.

Second threat


Monday, January 14, 2013

Gambetti et al USA Prion Unit change another highly suspect USA mad cow victim to another fake name i.e. sporadic FFI at age 16 CJD Foundation goes along with this BSe

Monday, December 31, 2012

Creutzfeldt Jakob Disease and Human TSE Prion Disease in Washington State, 2006–2011-2012

Saturday, December 29, 2012


Tuesday, December 25, 2012


Friday, November 23, 2012

sporadic Creutzfeldt-Jakob Disease update As at 5th November 2012 UK, USA, AND CANADA


JAMA. 2001;285(6):733-734. doi: 10.1001/jama.285.6.733

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Terry S. Singeltary, Sr Bacliff, Tex

Since this article does not have an abstract, we have provided the first 150 words of the full text.

KEYWORDS: creutzfeldt-jakob disease, diagnosis.

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

References 1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.

Published March 26, 2003

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States

Terry S. Singeltary, retired (medically)

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?

Published March 26, 2003


BY Philip Yam Yam Philip Yam News Editor Scientific American

Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.


Laying Odds

Are prion diseases more prevalent than we thought?

Researchers and government officials badly underestimated the threat that mad cow disease posed when it first appeared in Britain. They didn't think bovine spongiform encephalopathy was a zoonosis-an animal disease that can sicken people. The 1996 news that BSE could infect humans with a new form of Creutzfeldt-Jakob disease stunned the world. It also got some biomedical researchers wondering whether sporadic CJD may really be a manifestation of a zoonotic sickness. Might it be caused by the ingestion of prions, as variant CJD is?

Revisiting Sporadic CJD

It's not hard to get Terry Singeltary going. "I have my conspiracy theories," admitted the 49-year-old Texan.1 Singeltary is probably the nation's most relentless consumer advocate when it comes to issues in prion diseases. He has helped families learn about the sickness and coordinated efforts with support groups such as CJD Voice and the CJD Foundation. He has also connected with others who are critical of the American way of handling the threat of prion diseases. Such critics include Consumers Union's Michael Hansen, journalist John Stauber, and Thomas Pringle, who used to run the voluminous www.madcow. org Web site. These three lend their expertise to newspaper and magazine stories about prion diseases, and they usually argue that prions represent more of a threat than people realize, and that the government has responded poorly to the dangers because it is more concerned about protecting the beef industry than people's health.

Singeltary has similar inclinations. ...



Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9

June 2003 BY Philip Yam


Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.

14th ICID International Scientific Exchange Brochure -

Final Abstract Number: ISE.114

Session: International Scientific Exchange

Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

T. Singeltary

Bacliff, TX, USA


An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.


12 years independent research of available data


I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.


I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.


Human Prion Diseases in the United States

Robert C. Holman mail, Ermias D. Belay, Krista Y. Christensen, Ryan A. Maddox, Arialdi M. Minino, Arianne M. Folkema, Dana L. Haberling, Teresa A. Hammett, Kenneth D. Kochanek, James J. Sejvar, Lawrence B. Schonberger

CJD Singeltary submission to PLOS ;

No competing interests declared.

new link url ;

Wednesday, May 19, 2010

Molecular, Biochemical and Genetic Characteristics of BSE in Canada

>>> The occurrence of atypical cases of BSE in countries such as Canada with low BSE prevalence and transmission risk argues for the occurrence of sporadic forms of BSE worldwide. <<<

RE-Molecular, Biochemical and Genetic Characteristics of BSE in Canada

Posted by flounder on 19 May 2010 at 21:21 GMT


>>> The occurrence of atypical cases of BSE in countries such as Canada with low BSE prevalence and transmission risk argues for the occurrence of sporadic forms of BSE worldwide. <<<

In my opinion ;

THE statement above is about as non-scientific as a statement can be. There is no proof what-so-ever that any of the atypical BSE cases or atypical scrapie cases anywhere on the globe was a spontaneous case without any route and source of the TSE agent. This is a myth. The USDA and the OIE are trying to make the atypical BSE cases and they have already made the atypical Scrapie cases a legal trading commodity, without any transmission studies first confirming that in fact these atypical TSE will not transmit via feed. I suppose it is a human transmission study in progress. IT's like what happened in England with c-BSE and the transmission to humans via nvCJD never happened to the OIE and the USDA. Canada does not have a low prevalence of BSE either, they have a high prevalence. WHO knows about North America ? it's just that the U.S.A. try's much harder at concealing cases of mad cow disease. THIS was proven with the first stumbling and staggering mad cow in Texas, that was Wisk away to be rendered without any test at all. Then, you had the second case of mad cow disease that the USDA et al was almost as successful with as the first one, but the O.I.G. stepped in and demanded testing over seas, this after many scientist around the globe spoke out. Finally, after an act of Congress, the second case of mad cow disease in Texas was confirmed. all this was done for a reason, and that reason was the OIE USDA BSE MRR policy. Again, This study reeks of TRADE policy wrangling. There is NO proof that the atypical TSE are spontaneous. please show me these transmission studies ? on the other hand, we now know that the L-type atypical BSE is much more virulent than the typical C-BSE, and we now know that the H-type atypical BSE will transmit to humans. WHY can it not be that these atypical cases are simply from feed that had different strains of TSE ? WHY is it that no one will comment on the studies that was suppose to show infectivity of tissues from atypical BSE ? WHY is it I had to file a FOIA on that issue? L-type atypical BSE (BASE) is more virulent than classical BSE, has a lymphotropic phenotype, and displays a modest transmission barrier in our humanized mice. BSE-H is also transmissible in our humanized Tg mice. SEE Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1 et al 2009 ;

Atypical BSE, BSE, and other human and animal TSE in North America Update October 19, 2009


I ask Professor Kong ;

Thursday, December 04, 2008 3:37 PM

Subject: RE: re--Chronic Wating Disease (CWD) and Bovine Spongiform Encephalopathies (BSE): Public Health Risk Assessment

IS the h-BSE more virulent than typical BSE as well, or the same as cBSE, or less virulent than cBSE? just curious.....

Professor Kong reply ;


As to the H-BSE, we do not have sufficient data to say one way or another, but we have found that H-BSE can infect humans. I hope we could publish these data once the study is complete. Thanks for your interest.

Best regards, Qingzhong Kong, PhD Associate Professor Department of Pathology Case Western Reserve University Cleveland, OH 44106 USA

P.4.23 Transmission of atypical BSE in humanized mouse models

Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1 1Case Western Reserve University, USA; 2Instituto Zooprofilattico Sperimentale, Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research Institute, Poland; 5Kansas State University (Previously at USDA National Animal Disease Center), USA

Background: Classical BSE is a world-wide prion disease in cattle, and the classical BSE strain (BSE-C) has led to over 200 cases of clinical human infection (variant CJD). Atypical BSE cases have been discovered in three continents since 2004; they include the L-type (also named BASE), the H-type, and the first reported case of naturally occurring BSE with mutated bovine PRNP (termed BSE-M). The public health risks posed by atypical BSE were argely undefined.

Objectives: To investigate these atypical BSE types in terms of their transmissibility and phenotypes in humanized mice.

Methods: Transgenic mice expressing human PrP were inoculated with several classical (C-type) and atypical (L-, H-, or Mtype) BSE isolates, and the transmission rate, incubation time, characteristics and distribution of PrPSc, symptoms, and histopathology were or will be examined and compared.

Results: Sixty percent of BASE-inoculated humanized mice became infected with minimal spongiosis and an average incubation time of 20-22 months, whereas only one of the C-type BSE-inoculated mice developed prion disease after more than 2 years. Protease-resistant PrPSc in BASE-infected humanized Tg mouse brains was biochemically different from bovine BASE or sCJD. PrPSc was also detected in the spleen of 22% of BASE-infected humanized mice, but not in those infected with sCJD. Secondary transmission of BASE in the humanized mice led to a small reduction in incubation time. The atypical BSE-H strain is also transmissible with distinct phenotypes in the humanized mice, but no BSE-M transmission has been observed so far.

Discussion: Our results demonstrate that BASE is more virulent than classical BSE, has a lymphotropic phenotype, and displays a modest transmission barrier in our humanized mice. BSE-H is also transmissible in our humanized Tg mice. The possibility of more than two atypical BSE strains will be discussed.

Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.


Thursday, February 14, 2013

The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and TSE prion disease

with kindest regards,


MOM RIP 12/14/97 confirmed Heidenhain Variant Creutzfeldt Jakob Disease and her MOM and Brother died with Alzheimer’s...I can’t wait to see what happens...not.

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

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