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Astrocytes play crucial functions within neuronal circuits by providing metabolic and functional support, regulating interstitial solute composition, and modulating synaptic transmission. In addition to these physiological functions, growing evidence points to an essential role of astrocytes in neurodegenerative diseases like AD. Early\u2010stage AD is associated with hypometabolism and oxidative stress. Contrary to neurons that are vulnerable to oxidative stress, astrocytes are particularly resistant to mitochondrial dysfunction and are therefore more resilient cells. In our study, we leveraged astrocytic mitochondrial uncoupling and examined neuronal function in the 3xTg AD mouse model. We overexpressed the mitochondrial uncoupling protein 4 (UCP4), which has been shown to improve neuronal survival in vitro. We found that this treatment efficiently prevented alterations of hippocampal metabolite levels observed in AD mice, along with hippocampal atrophy and reduction of basal dendrite arborization of subicular neurons. This approach also averted aberrant neuronal excitability observed in AD subicular neurons and preserved episodic\u2010like memory in AD mice assessed in a spatial recognition task. These findings show that targeting astrocytes and their mitochondria is an effective strategy to prevent the decline of neurons facing AD\u2010related stress at the early stages of the disease.<\/jats:p>","DOI":"10.1002\/glia.24317","type":"journal-article","created":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T06:32:54Z","timestamp":1671517974000},"page":"957-973","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Overexpression of\n                    <scp>UCP4<\/scp>\n                    in astrocytic mitochondria prevents multilevel dysfunctions in a mouse model of Alzheimer's disease"],"prefix":"10.1002","volume":"71","author":[{"given":"Nadia","family":"Rosenberg","sequence":"first","affiliation":[{"name":"Department of Fundamental Neurosciences University of Lausanne  Lausanne 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