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While synaptic loss is a hallmark of AD, the molecular signals triggering pathological microglia-mediated synaptic engulfment remain elusive. Clec7a\u2014a key marker of disease-associated microglia (DAM)\u2014is known to activate spleen tyrosine kinase (SYK) signaling, enhancing A\u03b2 phagocytosis and neuroprotective functions in 5\u00d7FAD models. However, its role in regulating synapse\u2013microglia interactions under tauopathic conditions remains undefined. Our analysis revealed a progressive activation of the Clec7a\u2013SYK signaling axis in the hippocampus of PS19 tauopathy mice, correlating with disease progression. Spatial mapping demonstrated a significant co-localization of Clec7a with hippocampal microglia, suggesting cell-autonomous signaling. The pharmacological inhibition of Clec7a achieved multimodal therapeutic effects by attenuating microglial hyperreactivity, suppressing neuroinflammatory cytokine release, and restoring physiological synaptic turnover. Mechanistically, we identified MD2 as a synaptic \u201ceat-me\u201d signal on tauopathy-related synapses, recruiting Clec7a+ microglia to drive aberrant synaptic elimination in PS19 mice. Strikingly, Clec7a blockade rescued hippocampal-dependent memory deficits in behavioral tests. These findings position Clec7a as a context-dependent therapeutic target, with inhibition strategies showing particular promise for tauopathy-related synaptic degeneration.<\/jats:p>","DOI":"10.3390\/ijms26072888","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T07:46:50Z","timestamp":1742802410000},"page":"2888","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Clec7a Signaling in Microglia Promotes Synapse Loss Associated with Tauopathy"],"prefix":"10.3390","volume":"26","author":[{"given":"Shubing","family":"Yang","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan 430056, China"},{"name":"Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, 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