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Emerging evidence suggests that impaired microglial A\u03b2 phagocytosis is a key feature in AD, highlighting the therapeutic potential of enhancing this innate immune function. 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 metabolic fitness, 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":"10.1101\/2025.05.30.657101","type":"posted-content","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T01:10:16Z","timestamp":1748740216000},"source":"Crossref","is-referenced-by-count":9,"title":["PTP1B inhibition promotes microglial phagocytosis in Alzheimer\u2019s disease models by enhancing SYK signaling"],"prefix":"10.64898","author":[{"given":"Yuxin","family":"Cen","sequence":"first","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA"},{"name":"Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, New York 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9576-6444","authenticated-orcid":false,"given":"Steven R.","family":"Alves","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5076-4840","authenticated-orcid":false,"given":"Dongyan","family":"Song","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7772-2437","authenticated-orcid":false,"given":"Jonathan","family":"Preall","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0870-012X","authenticated-orcid":false,"given":"Linda","family":"Van Aelst","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2394-1538","authenticated-orcid":false,"given":"Nicholas K.","family":"Tonks","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041202410676000_2025.05.30.657101v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(21)00249-8"},{"key":"2026041202410676000_2025.05.30.657101v2.2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606210"},{"key":"2026041202410676000_2025.05.30.657101v2.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"2026041202410676000_2025.05.30.657101v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-7568(23)00193-9"},{"key":"2026041202410676000_2025.05.30.657101v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/s44319-024-00294-4"},{"key":"2026041202410676000_2025.05.30.657101v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2013.12.012"},{"key":"2026041202410676000_2025.05.30.657101v2.7","first-page":"1778","article-title":"Hypometabolism Exceeds Atrophy in Presymptomatic Early-Onset Familial Alzheimer\u2019s Disease","volume":"47","year":"2006","journal-title":"J. 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