Microglial CD31 Orchestrates Alzheimer’s Pathology via the SHP2–STAT3–MME Axis to Restrain Aβ Clearance

Here, we found that CD31 is predominantly expressed in microglia (rather than in neurons or astrocytes) and that its expression is notably elevated in microglia from AD patients and animal models. Microglia-specific knockdown of CD31 in 5xFAD mice significantly normalized the dysregulated expression of multiple gene sets in microglia.

This was accompanied by inhibited microglial hyperactivation, a reduced proportion of disease-associated microglia (DAM), decreased Aβ plaque deposition, mitigated inflammatory responses, alleviated synaptic damage, and ultimately improved cognitive functions. Mechanistically, these effects were mediated by reduced CD31-dependent recruitment of Src homology phosphatase 2 (SHP2), which led to a decreased dephosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) and thereby an enhanced activation.