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In tauopathies like Alzheimer's disease (AD), the abnormal accumulation of tau protein is initiated by pathological tau seeds. Mounting evidence implies that the microtubule binding domain, consisting of three to four repeats, plays a pivotal role in this process, yet the exact region driving the formation of pathogenic species needs to be further scrutinized. Here, we chemically synthesized individual tau repeats to identify those exhibiting pathogenic prion\u2010like characteristics. Notably, repeat 3 (R3) displayed a remarkable propensity to polymerize, form toxic filaments, and induce cognitive impairment, even in the absence of an aggregation\u2010promoting inducer, highlighting its physiological relevance. Additionally, oligomeric R3 was identified as a particularly pathological form, prompting the establishment of a screening platform. Through screening, tolcapone was found to possess therapeutic efficacy against pathological tau aggregates in PS19 transgenic mice. This screening platform provides a valuable avenue for identifying compounds that selectively interact with peptides implicated in the progression of tauopathies.<\/jats:p>","DOI":"10.1002\/anie.202411942","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T03:43:36Z","timestamp":1727149416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Drug Discovery and Screening Tool Development for Tauopathies by Focusing on Pathogenic Tau Repeat 3 Oligomers"],"prefix":"10.1002","volume":"63","author":[{"given":"Soljee","family":"Yoon","sequence":"first","affiliation":[{"name":"Department of Integrative Biotechnology Yonsei University  85 Songdogwahak-ro, Yeonsu-gu Incheon 21983 Republic of Korea"},{"name":"Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy Yonsei University  85 Songdogwahak-ro, Yeonsu-gu Incheon 21983 Republic of 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Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeyun","family":"Bhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy Yonsei University  85 Songdogwahak-ro, Yeonsu-gu Incheon 21983 Republic of Korea"},{"name":"Integrated Science and Engineering Division Yonsei University  85 Songdogwahak-ro, Yeonsu-gu Incheon 21983 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5029-7082","authenticated-orcid":false,"given":"YoungSoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Integrative Biotechnology Yonsei University  85 Songdogwahak-ro, Yeonsu-gu Incheon 21983 Republic of Korea"},{"name":"Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy Yonsei University  85 Songdogwahak-ro, Yeonsu-gu Incheon 21983 Republic of Korea"},{"name":"Department of 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