Oolonghomobisflavans fromCamellia sinensisdisaggregate tau fibrils across Alzheimer’s disease models

Abstract

ABSTRACTAlzheimer’s disease (AD) is a common debilitating neurodegenerative disease with limited treatment options. Amyloid-β (Aβ) and tau fibrils are well-established hallmarks of AD, which can induce oxidative stress, neuronal cell death, and are linked to disease pathology. Here, we describe the effects of Oolonghomobisflavan A (OFA) and Oolonghomobisflavan B (OFB) on tau fibril disaggregation and prionogenic seeding. Transcriptomic analysis of OF-treated animals reveals the induction of a proteostasis-enhancing and health-promoting signature. OFA treatment reduced the burden of Tau protein aggregation in aC. elegansmodel expressing pathogenic human tau (“hTau-expressing”) and promoted Tau disaggregation and inhibited seeding in assays usingex vivobrain-derived paired helical filament tau protein fibrils from Alzheimer’s disease brain donors. Correspondingly, treatment with OF improved multiple fitness and aging-related health parameters in the hTau-expressingC. elegansmodel, including reproductive output, muscle function, and importantly, reversed the shortened lifespan stemming from pathogenic Tau expression. Collectively, this study provides new evidence supporting the neuroprotective effects of OFs and reveal a new therapeutic strategy for targeting AD and other neurodegenerative diseases characterized by tauopathy.