title: Serial propagation of distinct strains of Aβ prions from Alzheimer's disease patients.
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.
authors: Institute for Neurodegenerative Diseases andDepartments of Neurology and.
authors: Joel C
authors: JC
authors: Watts
authors: Institute for Neurodegenerative Diseases and.
authors: Carlo
authors: C
authors: Condello
authors: Institute for Neurodegenerative Diseases andDepartments of Neurology and.
authors: Jan
authors: J
authors: Stöhr
authors: Pathology, University of California, San Francisco, CA 94143; and.
authors: Abby
authors: A
authors: Oehler
authors: Institute for Neurodegenerative Diseases and.
authors: Joanne
authors: J
authors: Lee
authors: Institute for Neurodegenerative Diseases andPathology, University of California, San Francisco, CA 94143; and.
authors: Stephen J
authors: SJ
authors: DeArmond
authors: Department of Public Health/Geriatrics, Uppsala University, 751 85 Uppsala, Sweden.
authors: Lars
authors: L
authors: Lannfelt
authors: Department of Public Health/Geriatrics, Uppsala University, 751 85 Uppsala, Sweden.
authors: Martin
authors: M
authors: Ingelsson
authors: Institute for Neurodegenerative Diseases andDepartments of Neurology and.
authors: Kurt
authors: K
authors: Giles
authors: Institute for Neurodegenerative Diseases andDepartments of Neurology and stanley@ind.ucsf.edu.
authors: Stanley B
authors: SB
authors: Prusiner
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011328:Prions
chemical_list: D016229:Amyloid beta-Peptides; D011328:Prions
keywords: bioluminescence imaging; neurodegeneration; proteinopathies; seeding