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Alliance"],"accepted":{"date-parts":[[2025,11,4]]},"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:p>\n                    Alzheimer\u2019s disease (AD) is a debilitating neurodegenerative disease hallmarked by the presence of amyloid-\u03b2 (A\u03b2) 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\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    model expressing pathogenic human tau (\u201chTau-expressing\u201d), but increase healthspan. Mechanistically, OFA treatment reduced the burden of tau protein aggregation and promoted tau disaggregation in hTau-expressing\n                    <jats:italic>C. elegans<\/jats:italic>\n                    and also inhibited seeding in assays using ex vivo brain-derived paired helical filament tau protein fibrils from Alzheimer\u2019s 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.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202503393","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T16:45:23Z","timestamp":1763397923000},"page":"e202503393","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Polyphyletic screen defines distinct classes of plant-derived natural products that oppose tauopathy"],"prefix":"10.26508","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1302-8980","authenticated-orcid":true,"given":"Chatrawee D","family":"Shepard","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02erqft81","id-type":"ROR","asserted-by":"publisher"}],"name":"The Appalachian Natural Products Research Program, Department of Biomedical Sciences, The Joan C. 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