EXCEED THE SPACE PROVIDED. LRP and Alzheimer disease This competing continuation application of a MERIT award studies the interplay of three proteins implicated in Alzheimer disease (AD) pathophysiology: the amyloid precursor protein (APP) and its product, At3, apolipoprotein E (apoE), a genetic risk factor and a modulator of AI3 clearance, and the low density lipoprotein receptor related protein (LRP), which is a receptor for both apoE and APP. Accumulation of AI3 in the brain is a central part of AD pathology. We proposed that LRP plays a major modulatory role in both AI3 clearance and Ai3 synthesis. LRP binds and acts as an endocytic cargo receptor for apo E/AI3 complexes. We have also discovered that APP directly interacts with LRP at both cytoplasmic and extracellular sites leading to its endocytosis. Blockade of APP-LRP interactions diminishes AI3. Our proposed studies take advantage of state of the art solid phase protein-protein interaction assays and fluorescence lifetime imaging FRET studies to examine these protein-protein interactions with isolated poteins and in intact cells. Using these techniques, new preliminary data suggest that LRP interacts not only with APP, but also with the APP processing enzymes BACE and gamma secretase. We will test the hypothesis that LRP acts as an organizing platform to bring APP together with its processing enzymes in rafts. LRP's interactions with APP and BACE depend on NPX domains in the cytoplasmic tail. Recently, several lines of evidence suggest that the cytoplasmic tail may serve an additional role in cell signaling. We have recently found that LRP acts as a co-receptor with the PDGF receptor. Stimulation activates a nonreceptor tyrosine kinase leading to phosphorylation of LRP's 2 nd NPXY domain. Moreover, separate experiments have shown that surprisingly LRP can be a substrate for gamma secretase and the cytoplasmic tail released from the membrane, analogous to observations with Notch and APP. We will test the hypothesis that ligand interactions or phosphorylaton events impact LRP's cleavage. The current application thus further explores APP-LRP interactions, identifies LRP-BACE and LRP-gamma secretase interactions, and further defines the potential role of LRP in cell signaling. The proposed studies aim to provide insight into the biology of LRP, APP and apoE, and their role in AD. PERFORMANCE SITE ========================================Section End===========================================
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