Clec7a Signaling in Microglia Promotes Synapse Loss Associated with Tauopathy

作者：Shubing Yang, Ji Wang, Yongkang Cao, Yibo Zhang, Zhuoran Sun, Pin Wan, Mingshan Pi, Qi Xiong, Xiji Shu, Xiaochuan Wang, Yiyuan Xia · 发表于：International Journal of Molecular Sciences · 年份：2025 · DOI：10.3390/ijms26072888 · 被引用次数：11 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Nuclear Receptors and Signaling、Alzheimer's disease research and treatments

Alzheimer's disease (AD) pathogenesis involves progressive synaptic degeneration, a process potentially driven by maladaptive microglial pruning activity. While synaptic loss is a hallmark of AD, the molecular signals triggering pathological microglia-mediated synaptic engulfment remain elusive. Clec7a-a key marker of disease-associated microglia (DAM)-is known to activate spleen tyrosine kinase (SYK) signaling, enhancing Aβ phagocytosis and neuroprotective functions in 5×FAD models. However, its role in regulating synapse-microglia interactions under tauopathic conditions remains undefined. Our analysis revealed a progressive activation of the Clec7a-SYK 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 "eat-me" 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 part...