Alzheimer?s disease (AD) is the most costly and devastating neurodegenerative disorder of the 21st century. To conquer AD, therapies must be developed to prevent the neuropathological manifestations of the disease. It is widely held that accumulation of beta amyloid (AB) plaques in AD brain causes oxidative damage and inflammatory responses involving glial cell activation that, in turn, leads to neuronal cell death. Many factors, including apolipoproteins, phospholipids and cholesterol, can influence aggregation of AB and its cytotoxic actions. There is evidence for the roles of plasma membrane lipids and G protein-coupled receptor functions in the cytotoxic effects of AB in the AD brain. The major loci of this Program Project Grant (PPG) are 1) to examine the effects of AB and oxidant stressors on neural cell functions relevant to the AD phenotype, including activation of phospholipases, cyclo-oxygenases and G protein-coupled receptors, and 2) to determine relationships between cholesterol homeostasis, lipoproteins and AD. This highly integrated PPG, directed by Dr. Grace Sun, consists of an Administrative Core, a Cell Culture Core and three research projects. Project #1 (G. Sun, PL) will determine the effects of AB and lipoproteins on oxidative and inflammatory responses in neural cells mediated by phospholipases A2. Project #2 (G. Weisman, PL) will determine the effects of AB and lipoproteins on G protein-coupled P2Y2 nucleotide receptor functions in glial and neuronal cells. Project #3 (G. Wood, PL) will determine how AB affects cholesterol homeostasis, transport and distribution in cell membranes and subcellular organelles. By understanding the role of lipids, lipoproteins, and receptor-mediated cell signaling pathways in AD pathology, the proposed studies will provide important new information that will impact the development of effective pharmacotherapies for this debilitating disease.
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