?-Synuclein Oligomers Induce a Unique Toxic Tau Strain.

ABSTRACT: BACKGROUND:The coexistence of ?-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 ?-synuclein in the tau aggregation pathway, we performed a set of experiments using both recombinant and brain-derived tau and ?-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 ?-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 ?-synuclein induced a distinct toxic tau oligomeric strain that avoids fibril formation. In vivo, Parkinson's disease brain-derived ?-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 ?-synuclein enhances the harmful effects of tau, thus contributing to disease progression.

SUBMITTER: Castillo-Carranza DL 

PROVIDER: S-EPMC6201292 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature