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Consequently, utilizing the intrinsic regulatory mechanisms of BACE1 during AD pathogenesis might provide valuable insights into the treatment of this devastating disease. In this study, we proposed a combination of AAV delivery and microRNA therapeutics targeting AD at its root by sustained and spatial inhibition of BACE1 with a single therapeutic injection. We demonstrate that upregulation of BACE1 is correlated with downregulation of miR-143-3p in the hippocampus of individuals with AD, and miR-143-3p can directly target BACE1 to inhibit A\u03b2 generation. In the brains of 5\u00d7FAD model mice, BACE1 levels are found to be elevated with age in the cornu ammonis 1 (CA1) subfield of the hippocampus. AAV-mediated miR-143-3p restoration in the hippocampal CA1 subfield of AD mice can improve cognitive performance, attenuate BACE1 expression, reduce A\u03b2 levels, induce microglia polarization toward the anti-inflammatory phenotype, modulate neural-related genes including Gal3, and promote synaptic functions. Collectively, the AAV-mediated microRNA gene therapy approach developed for spatial suppression of BACE1 can effectively enhance cognitive performance in AD model mice, offering an attractive therapeutic option for AD treatment with long-lasting efficacy.<\/jats:p>","DOI":"10.3390\/biom16081075","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T06:11:42Z","timestamp":1784787102000},"page":"1075","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development of a Novel AAV-Mediated microRNA Gene Therapy for Spatial Suppression of BACE1 to Improve Cognitive Function in Alzheimer\u2019s Disease Model Mice"],"prefix":"10.3390","volume":"16","author":[{"given":"Ying","family":"Zhou","sequence":"first","affiliation":[{"name":"College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuelin","family":"Diao","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases, Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhexiao","family":"Yan","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases, Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xindong","family":"Shui","sequence":"additional","affiliation":[{"name":"Key Laboratory of Non-Coding RNA and Drug Discovery, School of Basic Medical 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyao","family":"Wang","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases, Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqing","family":"Xia","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases, Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5968-1478","authenticated-orcid":false,"given":"Tae Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Fujian 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