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It's crucial to transform neurotoxic reactive astrocytes to neuroprotective phenotypes for the treatment of AD, particularly during the progression of the disease. In this study, we evaluated the role of nuclear factor E2\u2010related factor 2 (Nrf2) in facilitating the phenotype transformation of reactive astrocytes in\u00a0vivo and in\u00a0vitro by overexpressing Nrf2 in hippocampal astrocytes of 3xTg\u2010AD mice using adeno\u2010associated virus (AAV) vectors, as well as treating neurotoxic reactive astrocytes with dimethyl fumarate (a Nrf2 activator). We also evaluated the therapeutic effect of astrocyte\u2010specific Nrf2 in 3xTg\u2010AD mice with coexpression of A\u03b2 and tau pathologies. Our findings indicate that Nrf2 could facilitate the conversion of neurotoxic reactive astrocytes to neuroprotective phenotypes in\u00a0vivo and in\u00a0vitro. AAV\u2010mediated astrocyte\u2010specific Nrf2 expression improved cognitive function, reduced A\u03b2 and tau pathologies, rescued the loss of neurons and synapses, and ameliorated neuroinflammation in 3xTg\u2010AD mice. These findings highlighted the role of Nrf2 in modulating reactive astrocyte phenotypes and suggested the potential for utilizing AAV to target astrocyte\u2010specific Nrf2 as a promising therapeutic strategy for AD.<\/jats:p>","DOI":"10.1002\/glia.70087","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T07:37:16Z","timestamp":1759131436000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Astrocyte\u2010Specific Nrf2 Expression Transforms Neurotoxic Reactive Astrocytes to Neuroprotective Phenotype in\n                    <scp>3xTg<\/scp>\n                    \u2010\n                    <scp>AD<\/scp>\n                    Mice"],"prefix":"10.1002","volume":"74","author":[{"given":"Shenrui","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine Xinhua Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai 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