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Here, we demonstrate that genetic deletion or pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) ameliorated memory deficits and reduced A\u03b2 burden in APP\/PS1 mice. Moreover, we show that PTP1B was highly expressed in microglia, and its deficiency promoted a transcriptional shift toward immune activation and phagocytosis. Consistently, PTP1B deletion in microglia enhanced phagocytosis and energy metabolism, supported by increased AKT-mTOR signaling, a pathway essential for meeting the energy demands of activation. Mechanistically, we identified spleen tyrosine kinase (SYK), a key regulator of microglial phagocytosis, as a direct substrate of PTP1B. Inhibition of SYK showed that PTP1B modulates microglial activation in a SYK-dependent manner. These findings established PTP1B as a critical modulator of microglial activation and a potential therapeutic target for AD.<\/jats:p>","DOI":"10.1073\/pnas.2521944123","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T20:07:36Z","timestamp":1770062856000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["PTP1B inhibition promotes microglial phagocytosis in Alzheimer\u2019s disease models by enhancing SYK signaling"],"prefix":"10.1073","volume":"123","author":[{"given":"Yuxin","family":"Cen","sequence":"first","affiliation":[{"name":"Cold Spring Harbor Laboratory","place":["Cold Spring Harbor"]},{"name":"Graduate Program in Molecular and Cellular Biology, Stony Brook University","place":["Stony Brook"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9576-6444","authenticated-orcid":false,"given":"Steven","family":"R. 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