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Emerging evidence suggests that hypoxia\/ischemia-induced oxidative and endoplasmic reticulum (ER) stress may contribute to protein misfolding and \u03b1-Synuclein (\u03b1-Syn) aggregation, potentially triggering the unfolded protein response (UPR) to alleviate ER stress. Using bimolecular fluorescence complementation in\n                    <jats:italic>Drosophila melanogaster<\/jats:italic>\n                    and HEK-293 cells, we investigated the effect of acute, repetitive and chronic hypoxia on \u03b1-Syn aggregation, UPR activation, mortality, longevity, locomotor function, sleep, and cognition. Furthermore, we evaluated the post-hypoxic in vivo biodistribution and therapeutic efficacy of the aggregation inhibitor anle138b. Acute severe hypoxia induced more \u03b1-Syn aggregation than chronic or repetitive hypoxia, resulting in higher mortality, reduced longevity, delayed motor recovery, cognitive impairment, and activation of the detrimental PERK branch of the UPR. Anle138b significantly reduced \u03b1-Syn aggregation, repressing post-hypoxic PERK activation and improving survival and decision-making. Our findings demonstrate the effectiveness of anle138b in mitigating hypoxia-induced \u03b1-Syn aggregation and cognitive impairment, paving the way for future studies on its potential as a therapeutic strategy for PSCI.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1186\/s40478-025-02099-5","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T16:06:19Z","timestamp":1762877179000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Anle138b mitigates post-hypoxic cognitive impairment, \u03b1-Synuclein aggregation and UPR activation in Drosophila melanogaster"],"prefix":"10.1186","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1700-1184","authenticated-orcid":false,"given":"Aaron T.","family":"Fehr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-6059","authenticated-orcid":false,"given":"Jennifer","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1301-9472","authenticated-orcid":false,"given":"Alma","family":"Kokott-Vuong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9942-4580","authenticated-orcid":false,"given":"Sabri E. 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