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Current therapeutic interventions focus on the early stage of AD but lack effective treatment for the late stage of AD, largely due to the inability to replenish the lost neurons and repair the broken neural circuits. In this study, by using engineered adeno\u2010associated virus vectors that efficiently cross the blood\u2013brain\u2010barrier in the mouse brain, a brain\u2010wide neuroregenerative gene therapy is developed to directly convert endogenous astrocytes into functional neurons in a mouse model of AD. It is found that \u2248500\u00a0000 new neurons are regenerated and widely distributed in the cerebral cortex and hippocampus. Importantly, it is demonstrated that the converted neurons can integrate into pre\u2010existing neural networks and improve various cognitive performances in AD mice. Chemogenetic inhibition of the converted neurons abolishes memory enhancement in AD mice, suggesting a pivotal role for the newly converted neurons in cognitive restoration. Together, brain\u2010wide neuroregenerative gene therapy may provide a viable strategy for the treatment of AD and other brain disorders associated with massive neuronal loss.<\/jats:p>","DOI":"10.1002\/advs.202410080","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T11:11:37Z","timestamp":1739531497000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Brain\u2010Wide Neuroregenerative Gene Therapy Improves Cognition in a Mouse Model of Alzheimer's Disease"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3816-8891","authenticated-orcid":false,"given":"Zheng","family":"Wu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Key Laboratory of CNS Regeneration (Ministry of 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