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Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10329-34. doi: 10.1073/pnas.1408968111. Epub 2014 Jun 30.

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

Author information

1
Institute for Neurodegenerative Diseases,Departments of Neurology and.
2
Institute for Neurodegenerative Diseases.
3
Pathology, and.
4
Pharmaceutical Chemistry, University of California, San Francisco, CA 94143.
5
Institute for Neurodegenerative Diseases,Pathology, and.
6
Institute for Neurodegenerative Diseases,Departments of Neurology and stanley@ind.ucsf.edu.

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.

KEYWORDS:

Alzheimer's disease; in vitro; neurodegenerative diseases

PMID:
24982137
PMCID:
PMC4104853
DOI:
10.1073/pnas.1408968111
[Indexed for MEDLINE]
Free PMC Article

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