Cen, Yuxin, Alves, Steven R, Song, Dongyan, Preall, Jonathan, Van Aelst, Linda, Tonks, Nicholas K (June 2025) PTP1B inhibition promotes microglial phagocytosis in Alzheimer's disease models by enhancing SYK signaling. bioRxiv. ISSN 2692-8205 (Submitted)
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 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.
| Item Type: | Paper |
|---|---|
| Subjects: | organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > phagocytosis |
| CSHL Authors: | |
| Communities: | CSHL labs > Preall lab CSHL labs > Tonks lab CSHL labs > Van Aelst lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 8 June 2025 |
| Date Deposited: | 17 Jun 2025 12:54 |
| Last Modified: | 17 Jun 2025 12:54 |
| PMCID: | PMC12154680 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41889 |
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