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Astrocytes, main homeostatic cells in the CNS, represent promising cell\u2010target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD\u2010related memory deficits, neuropathology, and neuroinflammation. We have generated two, acute and chronic, AD mouse models with astrocytic CaNB1 ablation (ACN\u2010KO). In the former, we evaluated the ability of \u03b2\u2010amyloid oligomers (A\u03b2Os) to impair memory and activate glial cells once injected in the cerebral ventricle of conditional ACN\u2010KO mice. Next, we generated a tamoxifen\u2010inducible astrocyte\u2010specific CaNB1 knock\u2010out in 3xTg\u2010AD mice (indACNKO\u2010AD). CaNB1 was deleted, by tamoxifen injection, in 11.7\u2010month\u2010old 3xTg\u2010AD mice for 4.4\u2009months. Spatial memory was evaluated using the Barnes maze; \u03b2\u2010amyloid plaques burden, neurofibrillary tangle deposition, reactive gliosis, and neuroinflammation were also assessed. The acute model showed that ICV injected A\u03b2Os in 2\u2010month\u2010old wild type mice impaired recognition memory and fostered a pro\u2010inflammatory microglia phenotype, whereas in ACN\u2010KO mice, A\u03b2Os were inactive. In indACNKO\u2010AD mice, 4.4\u2009months after CaNB1 depletion, we found preservation of spatial memory and cognitive flexibility, abolishment of amyloidosis, and reduction of neurofibrillary tangles, gliosis, and neuroinflammation. Our results suggest that ACN is crucial for the development of cognitive impairment, AD neuropathology, and neuroinflammation. Astrocyte\u2010specific CaNB1 deletion is beneficial for both the abolishment of A\u03b2O\u2010mediated detrimental effects and treatment of ongoing AD\u2010related pathology, hence representing an intriguing target for AD therapy.<\/jats:p>","DOI":"10.1002\/glia.24509","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T09:35:24Z","timestamp":1706607324000},"page":"899-915","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Genetic deletion of astrocytic calcineurin <scp>B1<\/scp> prevents cognitive impairment and neuropathology development in acute and chronic mouse models of Alzheimer's disease"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8159-1628","authenticated-orcid":false,"given":"Laura","family":"Tapella","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences Universit\u00e0 del Piemonte Orientale  Novara 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