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Previously, we identified Trp-Leu-Pro (WLP), a novel antioxidant peptide derived from the sea squirt (Halocynthia roretzi); however, its effects on AD remained unexplored. In this study, we developed a rapid and efficient method to generate AD cerebral organoids with consistent quality using okadaic acid (OKA) exposure. This study aimed to evaluate the protective effects of WLP on OKA-induced AD pathology in cerebral organoids and elucidate its underlying mechanisms. Our results demonstrated that cerebral organoids exposed to 25 nM OKA successfully recapitulated hallmark AD pathologies, including amyloid-beta (A\u03b2) plaque deposits, neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau proteins, and neuronal loss. WLP treatment significantly enhanced cell viability, increased the proportion of neuronal progenitor cells, and reduced A\u03b2 plaques and NFTs in OKA-induced cerebral organoids. Furthermore, transcriptomic analysis revealed that the neuroprotective effects of WLP are primarily mediated through the regulation of synapse-related and oxidative stress pathways. These findings highlight the potential of WLP as a promising nutraceutical candidate for AD prevention.<\/jats:p>","DOI":"10.3390\/antiox14050553","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T04:20:26Z","timestamp":1746591626000},"page":"553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Sea Squirt-Derived Peptide WLP Mitigates OKA-Induced Alzheimer\u2019s Disease-like Phenotypes in Human Cerebral Organoid"],"prefix":"10.3390","volume":"14","author":[{"given":"Qiqi","family":"Chen","sequence":"first","affiliation":[{"name":"Molecular Toxicology Key Laboratory of Sichuan Provincial Education Office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, 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