Alzheimer's Disease (AD) is characterized by the extensive deposition of amyloid in the brain which elicits a robust microglial-mediated local inflammatory response that is linked to disease pathophysiology. Exposure of microglia to fibrillar forms of beta-amyloid (fAbeta) results in their activation and generation of a proinflammatory response. In the previous grant period we have shown that microglia employ a multi- receptor complex to detect and respond to Abeta fibrils. The principal elements of this complex are the alpha6beta1 integrin, the integrin associated protein CD47, the B-class scavenger receptor CD36, and scavenger receptor A. Moreover, we have dissected in detail the signal transduction pathways that emanate from the Abeta receptor complex that lead to the phenotypic activation of these cells. We have found that fAbeta stimulates signaling pathways that are typically employed by other immune stimuli. The conceptual advance represented by these studies is that i.) microglia use ensembles of receptors to respond to complex molecules such as fAbeta and ii.) the individual receptor elements signal in parallel to activate a diverse range of effectors. In this renewal application we propose to extend these studies to examine the participation of another putative constituent of the receptor complex and to establish exactly how the Abeta receptor complex is functionally linked to one of its effectors, the NADPH oxidase, to validate and verify our postulated receptor mechanism. We provide preliminary data that the Abeta receptor complex includes CD14, an unexpected role for this lipopolysaccharide (LPS) receptor. The participation of CD14 in Abeta-stimulated intracellular signaling will be investigated, and we will establish whether its signaling is reliant upon its canonical co-receptor TLR4. The effect of inactivation of the CD14 gene on microglial activation and amyloid pathology will be evaluated in an animal model of AD. Extensive oxidative damage is observed in the AD brain and in murine models of the disease. We have chosen to examine in detail how the Abeta receptor complex signals to stimulate the production of free radical oxidants through activation of the microglial NADPH oxidase. It remains controversial whether microglial NADPH oxidase is the principal source of reactive oxygen species in the AD brain or whether they derive from other sources. We propose to definitively test whether oxidative damage observed in an animal model of AD is due to NADPH oxidase action by examination of animals in which the oxidase has been genetically inactivated.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016740-10
Application #
7843572
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Petanceska, Suzana
Project Start
2000-03-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
10
Fiscal Year
2010
Total Cost
$268,538
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
Wilkinson, Brandy L; Cramer, Paige E; Varvel, Nicholas H et al. (2012) Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer's disease. Neurobiol Aging 33:197.e21-32
Cameron, Brent; Tse, Wayne; Lamb, Raza et al. (2012) Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer's disease. J Neurosci 32:15112-23
Mandrekar-Colucci, Shweta; Landreth, Gary E (2010) Microglia and inflammation in Alzheimer's disease. CNS Neurol Disord Drug Targets 9:156-67
Reed-Geaghan, Erin G; Reed, Quillan W; Cramer, Paige E et al. (2010) Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu. J Neurosci 30:15369-73
Lee, C Y Daniel; Landreth, Gary E (2010) The role of microglia in amyloid clearance from the AD brain. J Neural Transm (Vienna) 117:949-60
Cameron, Brent; Landreth, Gary E (2010) Inflammation, microglia, and Alzheimer's disease. Neurobiol Dis 37:503-9
Reed-Geaghan, Erin G; Savage, Julie C; Hise, Amy G et al. (2009) CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci 29:11982-92
Morgan, Dave; Landreth, Gary; Bickford, Paula (2009) The promise and perils of an Alzheimer disease vaccine: a video debate. J Neuroimmune Pharmacol 4:1-3
Mandrekar, Shweta; Jiang, Qingguang; Lee, C Y Daniel et al. (2009) Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J Neurosci 29:4252-62
Landreth, Gary; Jiang, Qingguang; Mandrekar, Shweta et al. (2008) PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease. Neurotherapeutics 5:481-9

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