Molecular Neurodegeneration, 2025

We investigated the role of microglial signaling adaptor DAP12. Although Dap12 deletion reduced microglial tau processing and increased tau accumulation—most prominently in females—it paradoxically protected against tau-induced synapse loss, demyelination, and neuroinflammation. Single-nucleus RNA sequencing showed that Dap12 deletion prevented tau-driven transcriptional changes across microglia, neurons, and oligodendrocytes. CellChat analysis revealed that tau pathology induces SLIT2 signaling from excitatory neurons to oligodendrocytes, promoting myelin loss. Dap12 deletion suppressed neuronal Slit2 upregulation and mitigated demyelination. Spatial transcriptomics revealed a spatial correlation of SLIT2 expression and tau pathology in AD brain tissue. Thus, modulation of a DAP12-dependent neuronal SLIT2–oligodendrocyte pathway underlies resilience to tau toxicity, suggesting that selectively dampening detrimental DAP12 signaling may enhance brain resilience in AD.

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