α-Synuclein Oligomers Induce a Unique Toxic Tau Strain

D.L. Castillo-Carranza, M.J. Guerrero-Muñoz, U. Sengupta, J.E. Gerson, R. Kayed

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

Background: The coexistence of α-synuclein and tau aggregates in several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease, raises the possibility that a seeding mechanism is involved in disease progression. Methods: To further investigate the role of α-synuclein in the tau aggregation pathway, we performed a set of experiments using both recombinant and brain-derived tau and α-synuclein oligomers to seed monomeric tau aggregation in vitro and in vivo. Brain-derived tau oligomers were isolated from well-characterized cases of progressive supranuclear palsy (n = 4) and complexes of brain-derived α-synuclein/tau oligomers isolated from patients with Parkinson's disease (n = 4). The isolated structures were purified and characterized by standard biochemical methods, then injected into Htau mice (n = 24) to assess their toxicity and role in tau aggregation. Results: We found that α-synuclein induced a distinct toxic tau oligomeric strain that avoids fibril formation. In vivo, Parkinson's disease brain–derived α-synuclein/tau oligomers administered into Htau mouse brains accelerated endogenous tau oligomer formation concurrent with increasing cell loss. Conclusions: Our findings provide evidence, for the first time, that α-synuclein enhances the harmful effects of tau, thus contributing to disease progression.

Original languageEnglish
Pages (from-to)499-508
Number of pages10
JournalBiological Psychiatry
Volume84
Issue number7
DOIs
Publication statusPublished - 1 Oct 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Michael J. Fox Foundation, the Cullen Trust, the Mitchell Center for Neurodegenerative Diseases, the Sealy Center for Vaccine Development, and National Institutes of Health Grant Nos. AG054025, RFA1AG055771, and NS094557 (to RK).

Publisher Copyright:
© 2018 Society of Biological Psychiatry

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

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