Alzheimer's Disease (AD) is typified by the presence of senile plaques and extensive neuronal loss. The senile plaque is comprised principally of extracellular deposits of beta-amyloid protein (betaAP) . The cellular source of the betaAP and the mechanism by which it accumulates in discrete deposits within the brain are unknown. A central controversy over the relevance of betaAP in AD is whether the senile plaque is a relic of a previous morbid event or is the focus of an ongoing and progressive pathological process. This proposal has as its principal objective to determine if betaAP elicits biological responses in cells of the central nervous system. We present preliminary data demonstrating that exposure of primary astrocytes , microglia or neurons to betaAP results in the rapid and dramatic increase in intracellular tyrosine phosphorylation. This observation is of importance as it indicates that betaAP activates intracellular signalling events typical of peptide hormone receptors. Similar effects are found with monocytes and macrophage cell lines. The enhanced protein tyrosine phosphorylation is maximal within 5-10 min. of treatment. In glial cells and monocytes/macrophages, an identical effect is observed with a peptide ligand for the serapin-enzyme complex (SEC) receptor. The latter is a newly recognized cell surface receptor which regulates tissue proteinase levels, but which also binds betaAP due to sequence similarity. Neurons fail to respond to the SEC ligand, in contrast to the glial cells.
The specific aims of this proposal are to identify and characterize the receptor interacting with betaAP on glial and neuronal cells. The identification of the tyrosine kinases which are activated upon betaAP exposure will be pursued in both neuronal and non-neuronal cells. The protein substrates of the betaAP-regulated kinases will be investigated. The capacity of betaAP to stimulate other components of the signal transduction cascade will be tested , including the activation of immediate early gene transcription and serine/threonine kinase activation. Finally, the ability of betaAP to provoke the acquisition of a """"""""reactive"""""""" phenotype in astrocytes and microglia will be tested including secretion and responsiveness to cytokines.
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