The Influences of ApoE Isoforms on Endothelial Adherens Junctions and Actin Cytoskeleton Responding to mCRP

Abstract

Monomeric C-reactive protein (mCRP) plays a role in cerebrovascular damage mediated by apolipoprotein E4 (ApoE4) in Alzheimer's disease (AD) pathogenesis. Using proteomic profilings, we found altered cytoskeleton proteins in the microvasculature of AD brains, including increased levels of hyperphosphorylated tau (pTau) and the actin-related protein, LIMA1. To address the hypothesis that cytoskeletal changes serve as early pathological signatures in brain endothelia for AD, ApoE4 knock-in mice intraperitoneal injected with mCRP revealed that mCRP bound to CD31 to increase LIMA1 expression and facilitate the binding of phosphorylated CD31 (pCD31) to LIMA1. mCRP combined with APOE4 protein altered the expression of various actin cytoskeleton proteins along with decreased interaction of CD31 and VE-Cadherin, causing microvasculature damage. Notably, the APOE2 protein attenuated these changes. Overall, the ApoE4-mCRP-CD31 pathway acts via pCD31-LIMA1 interaction to disrupt the adherens junctions and the actin cytoskeleton, leading to endothelial barrier dysfunction in the brain and increased AD risk.