PTP1B inhibition promotes microglial phagocytosis in Alzheimer's disease models by enhancing SYK signaling

Amyloid-ß (Aß) accumulation is a hallmark of Alzheimer's disease (AD). Emerging evidence suggests that impaired microglial Aß 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 Aß 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. Overall design: 13-month-old female mice from APP/PS1;PTP1B+/+ and APP/PS1;PTP1B-/- groups were sacrificed for the sample preparation. Mice were perfused with cold HBSS, and hippocampal tissues were dissociated in dissection buffer (DPBS Gibco, 14-287-080). Tissues dissociation was performed using the Adult Brain Dissociation Kit (Miltenyi Biotech, 130-107-677) according to the manufacturer's instructions, with manual trituration. Briefly, the chopped tissues were incubated in digestion buffer at 37 °C in a water bath for 15 min, with gently tapping of the tubes 3-4 times during the digestion. Following digestion, the tissues were triturated with fire-polished glass pipettes to obtain a single cell preparation, which was then filtered through a 70 µm cell strainer. To minimize ex vivo microglial activation, transcriptional and translational inhibitors were added in perfusion, dissection and digestion buffer as described (Marsh et al, doi: 10.1038/s41593-022-01022-8). In each sample, cells from two animals were pooled together.