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Metabolic dysfunctions, particularly type 2 diabetes mellitus (T2DM), have been implicated in AD pathogenesis, highlighting the potential for novel therapeutic approaches targeting shared underlying mechanisms. Here, we investigate sodium\u2010glucose cotransporter 2 (SGLT2) inhibition as a therapeutic strategy for AD using Enavogliflozin, a potent SGLT2 inhibitor, in the 5XFAD mouse model. Five\u2010month\u2010old 5XFAD mice were treated with Enavogliflozin (0.1 or 1\u2009mg\/kg) or vehicle for 8\u2009weeks. The higher dose significantly improved cognitive performance in Y\u2010maze and Morris Water Maze tests, which correlated with enhanced synaptic plasticity and increased acetylcholine levels. Moreover, Enavogliflozin treatment reduced A\u03b2 pathology and plaque burden, particularly affecting larger plaques. Mechanistically, SGLT2 inhibition attenuated neuroinflammation by suppressing NF\u2010\u03baB signaling and proinflammatory cytokine production while promoting microglial recruitment to plaques. In\u00a0vitro and ex\u00a0vivo analyses further revealed that Enavogliflozin enhances microglial phagocytic capacity via AMPK\u2010mediated mitochondrial biogenesis and function. These findings highlight the multifaceted neuroprotective effects of SGLT2 inhibition in AD, demonstrating its potential to mitigate pathology and improve cognitive function. By uncovering its impact on neuroinflammation and microglial function, this study establishes SGLT2 inhibition as a promising therapeutic avenue for AD and other neurodegenerative disorders.<\/jats:p>","DOI":"10.1111\/acel.70101","type":"journal-article","created":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T04:25:57Z","timestamp":1746851157000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["SGLT2 Inhibition by Enavogliflozin Significantly Reduces A\u03b2 Pathology and Restores Cognitive Function via Upregulation of Microglial AMPK Signaling in 5XFAD Mouse Model of Alzheimer's Disease"],"prefix":"10.1111","volume":"24","author":[{"given":"Jihui","family":"Han","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences, College of Medicine Seoul National University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaehoon","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences, College of Medicine Seoul National University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Sun","family":"Jung","sequence":"additional","affiliation":[{"name":"Convergence Dementia Research Center, College of Medicine Seoul National University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Won","family":"Choi","sequence":"additional","affiliation":[{"name":"Life Science Institute Daewoong Pharmaceutical  Yongin Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Young","family":"Ji","sequence":"additional","affiliation":[{"name":"Life Science Institute Daewoong Pharmaceutical  Yongin Republic of 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