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

## TL;DR

Reducing CD31 levels in mice with Alzheimer's disease improves memory and reduces key disease features like amyloid plaques and neuroinflammation.

## Contribution

CD31 is newly identified as a therapeutic target in Alzheimer's disease, with knockdown shown to reverse multiple disease hallmarks.

## Key findings

- CD31 is upregulated in Alzheimer's brains and transgenic mice, correlating with disease pathology.
- Knockdown of CD31 improves cognitive function and reduces amyloid and tau pathologies in 5xFAD mice.
- CD31 knockdown suppresses neuroinflammation by modulating STAT1/IRF1 signaling and gene expression.

## 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.

CD31 upregulation in 5xFAD mice activates STAT1/Irf1 signaling, driving abnormal gene transcription, Aβ and tau accumulation, microglial activation, and neuroinflammation, leading to cognitive decline. Systemic CD31 knockdown suppresses STAT1/Irf1 activity, restores gene expression balance, reduces Aβ and tau pathologies, alleviates neuroinflammation, and improves learning and memory in Alzheimer's disease.