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MicroRNA-33 (miR-33) has emerged as a key regulator of lipid homeostasis, yet its role in sAD remains unclear. This study investigated miR-33 dysregulation in APOE \u03b54 allele (ApoE4)-associated sAD and explored its therapeutic potential using clustered regulatory interspaced short palindromic repeats (CRISPR)-mediated gene editing.<\/jats:p>\n                  <jats:p>Elevated miR-33 expression was observed in both AD patients, particularly those with ApoE4-associated sAD, and in the ApoE4 mouse model, implicating its role in AD pathology. Using CRISPR\/Cas9, we modulated miR-33 expression in astrocytes to regulate ApoE lipidation and ameliorate AD-related pathology. Our results show that targeted miR-33 regulation in astrocytes via CRISPR\/Cas9 restores ApoE lipidation and mitigates AD pathology in both in vitro and in vivo AD mice. Additionally, applying this gene therapy approach in ApoE4 sAD patient cell lines highlights its translational potential for therapeutic intervention.<\/jats:p>\n                  <jats:p>In conclusion, our findings elucidate miR-33\u2019s role in AD pathogenesis and underscore the therapeutic promise of CRISPR-mediated miR-33 targeting for restoring lipid homeostasis and ameliorating AD pathology. This study provides valuable insights into developing miRNA-based gene therapy strategies for treating sAD.<\/jats:p>","DOI":"10.1093\/brain\/awaf244","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T07:43:06Z","timestamp":1751355786000},"page":"4400-4415","source":"Crossref","is-referenced-by-count":4,"title":["CRISPR editing of miR-33 restores ApoE lipidation and amyloid-\u03b2 metabolism in ApoE4 sporadic Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"148","author":[{"given":"Boyoung","family":"Kim","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Genetics, College of Pharmacy, Chungbuk National University , Cheongju 28160 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minju","family":"Yuk","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungbuk National University , Cheongju 28160 ,","place":["Republic of 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