Alzheimer's Disease (AD) is characterized by the extracellular deposition of compacted fibrillar forms of B-amyloid (AB) protein within the brain. These senile plaques are the focus of a complex cellular reaction, the most prominent which is the presence of abundant reactive microglial cells that are found adjacent to and invest in the senile plaques. Microglia are derived from a monocytic lineage and are the sole immune cell in the brain. Microglial activation is accompanied by enhanced expression of numerous cell surface proteins an elaboration of a complex array of proinflammatory and acute phase products. There is compelling evidence that there is a significant inflammatory component in Alzheimer's disease as evidenced by a diverse range of clinical studies which have shown that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) substantially reduces the incidence of AD-related dementia delays disease progression. The central hypothesis guiding these studies is that microglia can detect and respond to fibrillar forms of amyloid by activation of intracellular signaling pathways which subserve the """"""""activation"""""""" of the cells and the consequent secretion of proinflammatory products.
The Specific Aims of this proposal are: 1. The characterization of membrane proteins that interact with AB fibrils and serve as primary signal transducing elements linked to intracellular signaling pathways. We demonstrate that the B-class scavenger receptor, CD36, and an integrin mediate the adhesion of monocytes to AB fibrils and activation of tyrosine kinase based signaling cascades. We propose to identify the relevant integrin and ascertain how these cell surface molecules are linked to intracellular signal transduction complexes. 2. Identification of the signal transduction pathways activated in response to AB which subserve the production of proinflammatory products and the acquisition of an activated phenotype by the microglia. Specifically, we will investigate signaling pathways that mediate the activation of the transcription factors NFkB and the peroxisome proliferation activated receptor, PPARy. We will also investigate AB-inducted expression of cyclooxygenase-2. 3. We propose to employ an animal model of Alzheimer's disease to the effects of anti-inflammatory drugs on microglial activation. Transgenic mice expressing mutant forms of both the amyloid precursor gene and the presenelin 1 gene develop amyloid plaques and exhibit dramatic activation of plaque-associated microglia. We will test the efficacy of the classical NSAID, indomethacin, as well a PPARy agonists and a COX-2 specific inhibitor in blocking the acquisition of a reactive phenotype by microglial cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG016740-01A1
Application #
6044286
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Snyder, D Stephen
Project Start
2000-03-01
Project End
2005-01-31
Budget Start
2000-03-01
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$298,171
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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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
Cameron, Brent; Landreth, Gary E (2010) Inflammation, microglia, and Alzheimer's disease. Neurobiol Dis 37:503-9
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
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
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
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
Landreth, Gary E (2009) Microglia in central nervous system diseases. J Neuroimmune Pharmacol 4:369-70

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