Fibrillar β-Amyloid-stimulated Intracellular Signaling Cascades Require Vav for Induction of Respiratory Burst and Phagocytosis in Monocytes and Microglia

摘要: Microglial interaction with extracellular β-amyloid fibrils (fAβ) is mediated through an ensemble of cell surface receptors, including the B-class scavenger receptor CD36, α6β1-integrin, and integrin-associated protein/CD47. The binding fAβ to this complex has been shown drive a tyrosine kinase-based signaling cascade leading production reactive oxygen species stimulation phagocytic activity; however, little known about intracellular cascades governing microglial response fAβ. This study reports direct mechanistic link between downstream events responsible for NADPH oxidase activation phagosome formation. Vav guanine nucleotide exchange factor tyrosine-phosphorylated in peptides as result engagement microglia complex. Co-immunoprecipitation studies demonstrate Aβ-dependent association both Lyn Syk kinases. target Vav, small GTPase Rac1, GTP-loaded manner. Rac1 essential component critical regulator phagocytosis. role fAβ-stimulated was established using primary obtained from Vav–/– mice. Stimulation failed generate oxidase-derived displayed dramatically attenuated response. These findings directly phosphorylation Aβ-receptor that activity required upstream