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J. Biol. Chem., Vol. 281, Issue 30, 20842-20850, July 28, 2006

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

From the Alzheimer Research Laboratory, Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Microglial interaction with extracellular -amyloid fibrils (fA) is mediated through an ensemble of cell surface receptors, including the B-class scavenger receptor CD36, the ₆₁-integrin, and the integrin-associated protein/CD47. The binding of fA 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 fA. This study reports a direct mechanistic link between the fA 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 fA peptides as a result of the engagement of the microglia fA cell surface receptor complex. Co-immunoprecipitation studies demonstrate an A-dependent association between Vav and both Lyn and Syk kinases. The downstream target of Vav, the small GTPase Rac1, is GTP-loaded in an A-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 fA-stimulated intracellular signaling cascades was established using primary microglia obtained from Vav^–/– mice. Stimulation of Vav^–/– microglia with fA failed to generate NADPH oxidase-derived reactive oxygen species and displayed a dramatically attenuated phagocytic response. These findings directly link Vav phosphorylation to the A-receptor complex and demonstrate that Vav activity is required for fA-stimulated intracellular signaling events upstream of reactive oxygen species production and phagosome formation.

Received for publication, January 23, 2006 , and in revised form, May 23, 2006.

^* This work was supported in part by National Institutes of Health Grant AG16740, the Blanchette Hooker Rockefeller Foundation, and the American Health Assistance Foundation (to G. E. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by a Ruth L. Kirschstein National Research Service Award, National Institutes of Health Grant F32 AG24031. To whom correspondence should be addressed: Dept. of Neuroscience, Case Western Reserve University, SOM E504, 2109 Adelbert Rd., Cleveland, OH 44106. Tel.: 216-368-3435; Fax: 216-368-3079; E-mail: blw9{at}po.cwru.edu.

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