Oolonghomobisflavans from disaggregate tau fibrils across Alzheimer's disease models.

Alzheimer'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 a model expressing pathogenic human tau ("hTau-expressing") and promoted Tau disaggregation and inhibited seeding in assays using brain-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-expressing model, 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.