FIGURE 8.

A model illustrating the differential responses of ApoE2 vs. ApoE4 carriers to mCRP and the differential regulation of mCRP‐induced cerebrovascular neuroinflammation leading to AD pathogenesis in the brain. This study demonstrated a novel pathological mechanism, the competition of ApoE and mCRP to CD31binding, for cerebrovascular neuroinflammation resulting in an early stage of AD pathogenesis in the brain. During the chronic stage of peripheral inflammation, pCRP proteins disassociate into mCRP. mCRP binds to CD31 on blood‐facing endothelia to increase CD31 phosphorylation (pCD31), cause damage to the cerebrovasculature and induce extravasation of T lymphocytes into the brain, leading to AD pathogenesis (ApoE4>ApoE3>ApoE2). This process is antagonized by ApoE‐CD31 binding (ApoE2>ApoE3>ApoE4) to block mCRP‐CD31 binding and differentially regulate pathways (mitochondrial function, epigenetics and vasculogenesis) to intervene in the neurodegenerative process of AD