ArticleProceedings of the National Academy of Sciences of the United States of America2026
PTP1B inhibition promotes microglial phagocytosis in Alzheimer's disease models by enhancing SYK signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- A Covalent Resveratrol-Polyoxometalate Hybrid for Synergistic Disassembly of Prion Protein Fragment 106-126 Aggregates and Catalytic Scavenging of Reactive Oxygen Species.Small (Weinheim an der Bergstrasse, Germany) · 2026Article
- Microglia in Alzheimer's Disease: From Homeostatic Guardians to Multifaceted Drivers of Neuropathology.Cells · 2026Review
- Ganaxolone, an approved therapy for CDKL5-deficiency disorder, is an inhibitor of PTP1B.The Journal of biological chemistry · 2026Article
- Shifting paradigms: phosphatases from basic biology to druggable targets.Biology open · 2026Article
- PTP1B inhibition promotes microglial phagocytosis in Alzheimer's disease models by enhancing SYK signaling.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Dysregulated glucose metabolism in the visual cortex of human subjects with mild cognitive impairment and Alzheimer's disease.Frontiers in aging neuroscience · 2026Article
- Regulators of interferon-responsive microglia uncovered by Genome-wide CRISPRi screening.NPJ dementia · 2026Article
- Alzheimer's disease in theFree neuropathology · 2026Article
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7 authors.
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Abstract
Amyloid β (Aβ) accumulation is a hallmark of Alzheimer's disease (AD). Emerging evidence suggests that impaired microglial Aβ 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 Aβ 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.
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