Mini-Review
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: hsiao005@umn.edu
Adriano Aguzzi Institute of Neuropathology; University Hospital Zurich;
Zurich, Switzerland
Abstract:
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.
snip...
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).
snip...
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.
SNIP...SEE FULL TEXT ;
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
ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions
David W. Colby1,* and Stanley B. Prusiner1,2
SCENARIO 3: ‘THE THIN STEMMED GLASS’
Sustainable Production and Fragile Markets
Canada
Science
- 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.
SNIP...SEE FULL TEXT ;
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.
Abstract
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
CASE REPORTS CREUTZFELDT-JAKOB DISEASE: AN UNDER-RECOGNIZED CAUSE OF
DEMENTIA
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.
TSS
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