Tuesday, July 1, 2014

Distinct synthetic Aβ prion strains producing different amyloid deposits in bigenic mice

Distinct synthetic Aβ prion strains producing different amyloid deposits in bigenic mice

Jan Stöhra,b, Carlo Condelloa, Joel C. Wattsa,b,1, Lillian Blocha, Abby Oehlerc, Mimi Nickd, Stephen J. DeArmonda,c, Kurt Gilesa,b, William F. DeGradod, and Stanley B. Prusinera,b,2 Author Affiliations

aInstitute for Neurodegenerative Diseases, Departments of bNeurology and cPathology, and dPharmaceutical Chemistry, University of California, San Francisco, CA 94143 Contributed by Stanley B. Prusiner, May 14, 2014 (sent for review April 15, 2014)

Abstract Authors & Info SI Metrics PDF PDF + SI Significance Alzheimer’s disease is the most common neurodegenerative disorder; it is a progressive dementia for which there is currently no effective therapeutic intervention. The brains of patients with Alzheimer’s disease exhibit numerous amyloid β (Aβ) amyloid plaques and tau-laden neurofibrillary tangles. Our studies show that synthetic Aβ peptides can form prions that infect mice and induce Aβ amyloid plaque pathology. Two different Aβ prion strains were produced from Aβ peptides. When injected into transgenic mice, one Aβ strain produced large plaques and the other strain induced small but more numerous plaques. Our findings may help to delineate the molecular pathogenesis of Alzheimer’s disease and the development of anti-Aβ prion therapeutics.

Abstract An increasing number of studies continue to show that the amyloid β (Aβ) peptide adopts an alternative conformation and acquires transmissibility; hence, it becomes a prion. Here, we report on the attributes of two strains of Aβ prions formed from synthetic Aβ peptides composed of either 40 or 42 residues. Modifying the conditions for Aβ polymerization increased both the protease resistance and prion infectivity compared with an earlier study. Approximately 150 d after intracerebral inoculation, both synthetic Aβ40 and Aβ42 prions produced a sustained rise in the bioluminescence imaging signal in the brains of bigenic Tg(APP23:Gfap-luc) mice, indicative of astrocytic gliosis. Pathological investigations showed that synthetic Aβ40 prions produced amyloid plaques containing both Aβ40 and Aβ42 in the brains of inoculated bigenic mice, whereas synthetic Aβ42 prions stimulated the formation of smaller, more numerous plaques composed predominantly of Aβ42. Synthetic Aβ40 preparations consisted of long straight fibrils; in contrast, the Aβ42 fibrils were much shorter. Addition of 3.47 mM (0.1%) SDS to the polymerization reaction produced Aβ42 fibrils that were indistinguishable from Aβ40 fibrils produced in the absence or presence of SDS. Moreover, the Aβ amyloid plaques in the brains of bigenic mice inoculated with Aβ42 prions prepared in the presence of SDS were similar to those found in mice that received Aβ40 prions. From these results, we conclude that the composition of Aβ plaques depends on the conformation of the inoculated Aβ polymers, and thus, these inocula represent distinct synthetic Aβ prion strains.

Alzheimer's disease in vitro neurodegenerative diseases Footnotes ↵1Present address: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.


↵2To whom correspondence should be addressed. E-mail: stanley@ind.ucsf.edu. Author contributions: J.S., C.C., and S.B.P. designed research; J.S., C.C., J.C.W., L.B., A.O., and M.N. performed research; J.S., C.C., S.J.D., K.G., W.F.D., and S.B.P. analyzed data; and J.S. and S.B.P. wrote the paper.


The authors declare no conflict of interest.


This article contains supporting information online at



Prions causing neurodegeneration: A unifying etiology and the quest for therapeutics
Stanley B Prusiner University of California, Institute for Neurodegenerative Diseases; San Francisco, CA, USA
Mounting evidence argues that prions feature in the pathogenesis of many, if not all, neurodegenerative diseases. Such disorders include Alzheimer’s, Parkinson’s, Lou Gehrig’s and Creutzfeldt-Jakob diseases as well as the frontotemporal dementias. In each of these illnesses, aberrant forms of a particular protein accumulate as pathological deposits referred to as amyloid plaques, neurofibrillary tangles, Lewy bodies, as well as glial cytoplasmic and/or nuclear inclusions. The heritable forms of the neurodegenerative diseases are often caused by mutations in the genes encoding the mutant, prion proteins that accumulate in the CNS of patients with these fatal disorders. The late onset of the inherited neurodegenerative diseases seems likely to be explained by the protein quality control systems being less efficient in older neurons and thus, more permissive for prion accumulation. To date, there is not a single drug that halts or even slows one neurodegenerative disease.
Prusiner SB. Biology and genetics of prions causing neurodegeneration. Annu Rev Genet 2013; 47:601-23; PMID:24274755; http://dx.doi.org/10.1146/ annurev-genet-110711-155524
Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 2013; 501:45-51; PMID:24005412; http://dx.doi. org/10.1038/nature12481
Wednesday, April 2, 2014
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