The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer's disease pathology

In Alzheimer's disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. While extrinsic signals including interleukin-33 (IL-33) can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor(s) is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aß) plaque-associated ApoE, and leads to Aß clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aß-directed migration. Functional screening identified that VCAM1 directs microglial Aß chemotaxis by sensing Aß plaque-associated ApoE. Moreover, we found that disrupting VCAM1–ApoE interaction abolishes microglial Aß chemotaxis, resulting in decreased microglial clearance of Aß. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aß chemotaxis. Together, our findings demonstrate that promoting VCAM1–ApoE-dependent microglial functions ameliorates AD pathology. Overall design: FACS-isolated microglia in IL-33-treated AD transgenic mice