title: Fibrillar beta-amyloid-stimulated intracellular signaling cascades require Vav for induction of respiratory burst and phagocytosis in monocytes and microglia.
abstract: Microglial interaction with extracellular beta-amyloid fibrils (fAbeta) is mediated through an ensemble of cell surface receptors, including the B-class scavenger receptor CD36, the alpha(6)beta(1)-integrin, and the integrin-associated protein/CD47. The binding of fAbeta to this receptor complex has been shown to drive a tyrosine kinase-based signaling cascade leading to production of reactive oxygen species and stimulation of phagocytic activity; however, little is known about the intracellular signaling cascades governing the microglial response to fAbeta. This study reports a direct mechanistic link between the fAbeta cell surface receptor complex and downstream signaling events responsible for NADPH oxidase activation and phagosome formation. The Vav guanine nucleotide exchange factor is tyrosine-phosphorylated in response to fAbeta peptides as a result of the engagement of the microglia fAbeta cell surface receptor complex. Co-immunoprecipitation studies demonstrate an Abeta-dependent association between Vav and both Lyn and Syk kinases. The downstream target of Vav, the small GTPase Rac1, is GTP-loaded in an Abeta-dependent manner. Rac1 is both an essential component of the NADPH oxidase and a critical regulator of microglial phagocytosis. The direct role of Vav in fAbeta-stimulated intracellular signaling cascades was established using primary microglia obtained from Vav(-/-) mice. Stimulation of Vav(-/-) microglia with fAbeta failed to generate NADPH oxidase-derived reactive oxygen species and displayed a dramatically attenuated phagocytic response. These findings directly link Vav phosphorylation to the Abeta-receptor complex and demonstrate that Vav activity is required for fAbeta-stimulated intracellular signaling events upstream of reactive oxygen species production and phagosome formation.
authors.affiliation: Alzheimer Research Laboratory, Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106. Electronic address: blw9@po.cwru.edu.
authors.forename: Brandy
authors.initials: B
authors.lastname: Wilkinson
authors.affiliation: Alzheimer Research Laboratory, Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Jessica
authors.initials: J
authors.lastname: Koenigsknecht-Talboo
authors.affiliation: Alzheimer Research Laboratory, Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Christian
authors.initials: C
authors.lastname: Grommes
authors.affiliation: Alzheimer Research Laboratory, Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: C Y Daniel
authors.initials: CYD
authors.lastname: Lee
authors.affiliation: Alzheimer Research Laboratory, Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Gary
authors.initials: G
authors.lastname: Landreth
mesh_terms: D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D018955:CD36 Antigens / Q000096:biosynthesis; D051928:CD47 Antigen / Q000096:biosynthesis; D006801:Humans; D039121:Integrin alpha6beta1 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D016897:Respiratory Burst; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018955:CD36 Antigens; D051928:CD47 Antigen; D039121:Integrin alpha6beta1; D051567:Proto-Oncogene Proteins c-vav; D020830:rac1 GTP-Binding Protein