# Polyphyletic screen defines distinct classes of plant-derived natural products that oppose tauopathy

## TL;DR

This study identifies plant-derived compounds that reduce harmful tau protein buildup in Alzheimer's disease models and shows how they work.

## Contribution

A new screening strategy for tau-targeting compounds and the discovery of two distinct plant-derived natural products with unique mechanisms.

## Key findings

- OFA reduces tau aggregation and promotes disaggregation in C. elegans and inhibits seeding from AD brain fibrils.
- Plumbagin (PB) was identified as a potent inhibitor of tau monomer aggregation with a distinct mechanism from OFA.
- Treatment with OFA and OFB improves healthspan and reverses shortened lifespan in hTau-expressing C. elegans.

## Abstract

This study reveals a new strategy for identifying therapeutic compounds that target tauopathy and provides mechanistic insight supporting the neuroprotective effects of plant-derived natural products.

Alzheimer’s disease (AD) is a debilitating neurodegenerative disease hallmarked by the presence of amyloid-β (Aβ) plaques and tau fibrils but with limited treatment options. Here, we describe two plant-derived natural products with distinct mechanisms of action on tau fibril disaggregation and prionogenic seeding. We first characterized the effects of oolonghomobisflavan A (OFA) and oolonghomobisflavan B (OFB) treatments, which alter the transcriptional landscape toward enhanced proteostasis and reverse the shortened lifespan in a Caenorhabditis elegans model expressing pathogenic human tau (“hTau-expressing”), but increase healthspan. Mechanistically, OFA treatment reduced the burden of tau protein aggregation and promoted tau disaggregation in hTau-expressing C. elegans and also inhibited seeding in assays using ex vivo brain-derived paired helical filament tau protein fibrils from Alzheimer’s disease brain donors. We leveraged this finding to develop a facile screening approach for compounds, like OFA, that could mitigate tau aggregation, which revealed plumbagin (PB) as a potent inhibitor of tau monomer aggregation which is mechanistically distinct from the tau fibril disaggregase activity associated with OFA. Collectively, this study reveals a new strategy for identifying therapeutic compounds that target tauopathy and provides mechanistic insight supporting the neuroprotective effects of plant-derived natural products.