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This study unveiled a novel miRNA, microRNA\u201032533 (miR\u201032533), featuring a distinctive base sequence identified through RNA sequencing of the APPswe\/PSEN1dE9 (APP\/PS1) mouse brain. Its role and underlying mechanisms were subsequently explored. Bioinformatics and confirmatory experiments revealed that miR\u201032533 had a novel 23\u2010base sequence with minimal coding potential, functioning within the Drosha ribonuclease III (Drosha)\/Dicer 1, ribonuclease III (Dicer)\u2010dependent canonical pathway and identifiable via northern blot. miR\u201032533 was abundantly brain\u2010distributed and downregulated in diverse AD\u2010related models, including APP\/PS1 and\u00a0five familial AD (5\u00d7FAD) mouse brains and AD patient plasma. Overexpression or inhibition of miR\u201032533 led to improvements or exacerbations in cognitive dysfunction, respectively, by modulating A\u03b2\u00a0production, apoptosis, oxidation, and neuroinflammation through targeting cAMP\u2010responsive element binding protein 5\u00a0(CREB5), which interacted with \u03b1 disintegrin and metalloproteinase 10\u00a0(ADAM10), beta\u2010site amyloid precursor protein cleaving enzyme 1\u00a0(BACE1), and presenilin 1 (PS1) promoters, thereby enhancing A\u03b2 production through BACE1 and PS1 upregulation while suppressing non\u2010amyloidogenic amyloid precursor protein (APP) processing via ADAM10 downregulation. Furthermore, modulation of the miR\u201032533\/CREB5 axis ameliorated or worsened cognitive impairment by inhibiting or amplifying A\u03b2 overproduction through the BACE1\u2010involved amyloidogenic and ADAM10\u2010involved non\u2010amyloidogenic pathways. Overall, the findings suggest miR\u201032533 as a regulator of A\u03b2 metabolism, oxidative stress, and neuroinflammation, establishing the miR\u201032533\/CREB5 signaling pathways as potential therapeutic targets for combating A\u03b2 accumulation and cognitive deficits in AD.<\/jats:p>","DOI":"10.1002\/advs.202409986","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T05:31:27Z","timestamp":1737523887000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["miR\u201032533 Reduces Cognitive Impairment and Amyloid\u2010\u03b2 Overload by Targeting CREB5\u2010Mediated Signaling Pathways in Alzheimer's Disease"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8834-8885","authenticated-orcid":false,"given":"Li","family":"Zeng","sequence":"first","affiliation":[{"name":"Institute of Medicinal Biotechnology Peking Union Medical College and Chinese Academy of Medical Sciences  Beijing 100050 P. 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