Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice

Microglia play crucial roles in Alzheimer’s disease (AD), yet the molecular mechanisms are unclear. Here, we show that CD31, a recognized endothelial marker, is predominantly expressed in microglia but not in neurons or astrocytes, and it is significantly elevated in the brains of AD patients and mouse models. Microglia-specific CD31 knockdown in 5xFAD mice substantially attenuated the dysregulated transcription networks, suppressed microglia hyperactivation and the disease-associated microglia (DAM), mitigated Aβ deposition and inflammation, and eventually improved cognitive functions in mice. Mechanistically, CD31 knockdown damaged the simultaneous recruitment of Src homology phosphatase 2 (SHP2) and STAT3, leading to a reduced dephosphorylation and enhanced activation of STAT3, a transcription factor. STAT3 activation increased transcription of membrane metalloendopeptidase (MME) and promoted Aβ clearance. Collectively, this study identifies microglial CD31, by regulating SHP2–STAT3–MME axis, plays a role in AD pathogenesis and targeting CD31 is promising in AD drug development.