α-Synuclein Oligomers Induce a Unique Toxic Tau Strain

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.