The goal of this proposal is to elucidate mechanisms mediating the microglia pro-inflammatory response to fibrillar beta amyloid (fAa). The interaction of microglia with Abeta plaques leads to the induction of proinflammatory signaling cascades and the release of neurotoxic secretory products. Previous studies have shown fAbeta-stimulated ROS production from the activation of microglial NADPH oxidase. The NADPH oxidase consists of the membrane associated flavoprotein cytochrome b558 and the cytosolic, p47phox, p67phox, p40phox, and Rac1. Rac must be GTP-bound to function as part of the oxidase. The cytosolic components, p47phox and p67phox, under go phosphorylation and translocation to the membrane to initiate ROS generation. Little is known about the Abeta-stimulated intracellular signaling pathways responsible for this activation. We hypothesize that fAbeta engagement of a newly discovered multireceptor cell surface complex on microglia leads to the production of ROS and subsequent neuronal damage. This proposal seeks to identify tyrosine kinase-based signaling cascades that activate intracellular signaling elements that function to stimulate assembly and activation of the NADPH oxidase following exposure to fAbeta.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AG024031-03
Application #
7172922
Study Section
Special Emphasis Panel (ZRG1-F01 (20))
Program Officer
Snyder, Stephen D
Project Start
2004-11-01
Project End
2007-10-31
Budget Start
2006-12-15
Budget End
2007-10-31
Support Year
3
Fiscal Year
2007
Total Cost
$52,048
Indirect Cost
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Jiang, Qingguang; Lee, C Y Daniel; Mandrekar, Shweta et al. (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58:681-93
Wilkinson, Brandy; Koenigsknecht-Talboo, Jessica; Grommes, Christian et al. (2006) Fibrillar beta-amyloid-stimulated intracellular signaling cascades require Vav for induction of respiratory burst and phagocytosis in monocytes and microglia. J Biol Chem 281:20842-50