{"doi":"10.26508/lsa.202503393","title":"Polyphyletic screen defines distinct classes of plant-derived natural products that oppose tauopathy","abstract":"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.","journal":"Life Science Alliance","year":2025,"id":537186,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1323346,"name":"Xinmin Chang","orcid":"0009-0006-3295-6885","position":1,"is_corresponding":false},{"id":473677,"name":"Paul M. Seidler","orcid":"0000-0001-8530-7244","position":2,"is_corresponding":false},{"id":277109,"name":"Sean P. Curran","orcid":"0000-0001-7791-6453","position":3,"is_corresponding":false},{"id":746029,"name":"Chatrawee Duangjan","orcid":"0000-0002-1302-8980","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:52:12.997494Z","pmid":"41249005","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}