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Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10323-8. doi: 10.1073/pnas.1408900111. Epub 2014 Jun 30.

Serial propagation of distinct strains of Aβ prions from Alzheimer's disease patients.

Author information

  • 1Institute for Neurodegenerative Diseases andDepartments of Neurology and.
  • 2Institute for Neurodegenerative Diseases and.
  • 3Pathology, University of California, San Francisco, CA 94143; and.
  • 4Institute for Neurodegenerative Diseases andPathology, University of California, San Francisco, CA 94143; and.
  • 5Department of Public Health/Geriatrics, Uppsala University, 751 85 Uppsala, Sweden.
  • 6Institute for Neurodegenerative Diseases andDepartments of Neurology and stanley@ind.ucsf.edu.

Abstract

An increasing number of studies argues that self-propagating protein conformations (i.e., prions) feature in the pathogenesis of several common neurodegenerative diseases. Mounting evidence contends that aggregates of the amyloid-β (Aβ) peptide become self-propagating in Alzheimer's disease (AD) patients. An important characteristic of prions is their ability to replicate distinct strains, the biological information for which is enciphered within different conformations of protein aggregates. To investigate whether distinct strains of Aβ prions can be discerned in AD patients, we performed transmission studies in susceptible transgenic mice using brain homogenates from sporadic or heritable (Arctic and Swedish) AD cases. Mice inoculated with the Arctic AD sample exhibited a pathology that could be distinguished from mice inoculated with the Swedish or sporadic AD samples, which was judged by differential accumulation of Aβ isoforms and the morphology of cerebrovascular Aβ deposition. Unlike Swedish AD- or sporadic AD-inoculated animals, Arctic AD-inoculated mice, like Arctic AD patients, displayed a prominent Aβ38-containing cerebral amyloid angiopathy. The divergent transmission behavior of the Arctic AD sample compared with the Swedish and sporadic AD samples was maintained during second passage in mice, showing that Aβ strains are serially transmissible. We conclude that at least two distinct strains of Aβ prions can be discerned in the brains of AD patients and that strain fidelity was preserved on serial passage in mice. Our results provide a potential explanation for the clinical and pathological heterogeneity observed in AD patients.

KEYWORDS:

bioluminescence imaging; neurodegeneration; proteinopathies; seeding

PMID:
24982139
[PubMed - indexed for MEDLINE]
PMCID:
PMC4104857
Free PMC Article
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