Prions, prionoids and pathogenic proteins in Alzheimer disease

Volume 7, Issue 1 January/February 2013 Keywords: Alzheimer’s disease, PrP, amyloid-β, pathogenic proteins, prionoids, prions, tau Authors: Karen H. Ashe and Adriano Aguzzi View affiliations Hide affiliations Karen H. Ashe Corresponding author:

Adriano Aguzzi Institute of Neuropathology; University Hospital Zurich; Zurich, Switzerland


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.


In prion disease catastrophic brain dysfunction is associated with a global decrease in protein production, resulting from the dysregulation of eIF2a, a mammalian translation initiation factor.23 This fascinating discovery is presumably the mechanism by which PrP prions ultimately induce neurotoxicity.

However, eIF2a is localized within the cytosol whereas infectious prions are extracellular. Therefore, we are still left wondering how prions containing pathologically aggregated PrPSc can possibly exert actions that originate from the extracellular milieu, derange protein folding in the endoplasmic reticulum, induce a surprisingly vigorous unfolded protein response, and eventually quench cytosolic translation of proteins. It is hard not to conclude that eIF2a repression likely represents a downstream effector of a pathogenic cascade that is initiated by molecularly and topologically distant events.

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.


Wednesday, January 18, 2012

Government seeking $1T campaign against Alzheimer's

Monday, September 26, 2011

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

Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility

Wednesday, September 21, 2011

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

Researchers’ Discovery May Revolutionize Treatment of ALS


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)


Wednesday, January 5, 2011


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


Sustainable Production and Fragile Markets



- BSE is not linked to classical CJD, but a TSE is found that is linked to Alzheimer’s disease.

- Science breakthroughs in neurodegenerative diseases.

- New product development continues.


Sunday, December 2, 2012

CANADA 19 cases of mad cow disease SCENARIO 4: ‘WE HAD OUR CHANCE AND WE BLEW IT’

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.

Wednesday, May 16, 2012

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

Proposal ID: 29403

Terry S. Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis

full text with source references ;


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

Background: 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.

Methods: 12 years independent research of available data

Results: 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.

Conclusion: 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.

Friday, October 05, 2012

Differential Diagnosis of Jakob-Creutzfeldt Disease


Monday, August 20, 2012



see the Duke, Pa, Yale, and Mexican study here, showing the misdiagnosis of CJD TSE prion disease as Alzheimers ;

Letters| February 14, 2001

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Terry S. Singeltary, Sr

JAMA. 2001;285(6):733-734. doi:10-1001/pubs.JAMA-ISSN-0098-7484-285-6-jlt0214. Text Size: AA A Published online Article References

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.


Sunday, December 9, 2012

Prions, prionoids and pathogenic proteins in Alzheimer disease