Identification and characterization of the CD31-ApoE-mCRP pathway for Alzheimer's disease in humans.

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SUMMARY Our study discovered that elevated blood C-reactive protein (CRP) in Apolipoprotein E4 (ApoE4) carriers, but not in carriers of ApoE2 and ApoE3 alleles, increased the risk and shortened latency for Alzheimer’s disease (AD) onset (Tao et al. 2018). As both peripheral chronic inflammation and peripheral vascular disease increase AD risk, CRP is considered to be the major inflammatory response protein that mediates toxicity in peripheral vascular injuries/diseases through vascular endothelial cells. There are two species of CRP, pentameric oligoprotein (pCRP) and monomeric CRP (mCRP). Our preclinical study discovered that the receptor for mCRP, CD31 (Pecam1), is located on the blood-facing endothelial cells of the blood-brain barrier (BBB) and that mCRP acts to increase phosphorylation of the endothelial CD31 receptor (pCD31), transmitting signals and AD pathology in a pattern of ApoE4>ApoE3>ApoE2 (Zhang et al. 2021). However, whether mCRP is linked with cerebrovascular endothelial pathology leading to AD risk in humans is unclear. Our central hypothesis is that the mCRP-CD31 binding on brain endothelial cells will be associated with increased CD31 phosphorylation (pCD31) and neuroinflammation, with more severe cerebrovascular and AD pathologies, and with cognitive decline in an ApoE sensitive manner (ApoE4 > ApoE3 > ApoE2) in humans; this pathological process is counter acted by the ApoE-CD31 binding on endothelial cells in the brain. There are three aims. Aim 1 will establish the relationship between endothelial CD31 expression, CD31 phosphorylation and mCRP to AD risk in ApoE4 carriers using human brain tissues. Aim 2 will relate brain cerebrovascular expression of CD31, pCD31, and mCRP-CD31 and ApoE-CD31 bindings to incident cognitive change. Aim 3 will isolate microvessels from frozen brain tissues in each pathology group and apply phosphor-proteomics. We will further validate CD31 and its involved pathway(s) by using ApoE knock-in mice responding to peripheral elevated mCRP. Should our proposed study support the concept that mCRP through mCRP-CD31 vs. ApoE-CD31 binding is a mediating factor of ApoE4 to increase AD risk, it will lay foundation for a new, genetic based drug target for AD.