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.
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