Downregulating Platelet Endothelial Cell Adhesion Molecule‐1 Enhances Learning and Memory and Alleviates Hallmark Pathologies in Alzheimer's Disease

ABSTRACT Alzheimer's disease (AD) is a neurodegenerative disorder that currently lacks cures; thus, searching for new biomarkers and unraveling its underlying mechanisms are crucial for devising effective therapies. Here, we discovered that both mRNA and protein levels of CD31 (platelet endothelial cell adhesion molecule‐1, PECAM1), a transmembrane glycoprotein in immunoglobulin superfamily, were significantly higher in the brains of AD individuals and different AD transgenic mice, and the elevated CD31 was related to the recognized AD pathologies. Additional studies demonstrated that systemically knockdown of CD31 in 5xFAD mice significantly improved the cognitive functions with decreased AD hallmark pathologies, including β ‐amyloid precipitation and tau hyperphosphorylation. Moreover, CD31 knockdown alleviated neuroinflammation, evidenced by the diminished microglial stimulation and suppressed expression of pro‐inflammatory cytokines. Transcriptomic analysis indicated considerable changes in the AD‐involved gene expression in 5xFAD mice, and CD31 knockdown rectified imbalanced gene expression. Mechanistically, we further revealed that CD31 knockdown suppressed the expression of STAT1 and IRF1 by reducing histone lactylation at H3K14 and H4K12, thereby modulating the transcriptional programs driving neuroinflammation and AD pathology. These findings illustrate that CD31 may act as a promising target for creating novel therapeutic strategies.