Abnormal Low Density Lipoprotein Receptor Localization and Function in AD

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DESCRIPTION (provided by applicant): We seek to elucidate the interactive roles that atherosclerosis and Abeta play in the pathogenesis of co-morbid Alzheimer's disease (AD) and vascular dementia. Although, most of the field's efforts have been focused on the role of LDL, ApoE and their receptors play in AD pathogenesis, we have obtained evidence that APP/Abeta alters the expression and localization of the LDLR, such that it becomes concentrated in single perinuclear aggregate, rather than sorting to the cell surface. Other experiments suggest that Abeta induces a general defect in the MT network that likely leads to the mis-localization of some, but not all membrane proteins, including the LDLR, potentially rendering it (them) less active. We therefore propose to Test the Hypotheses that 1. APP/Abeta affects LDLR expression and intracellular localization. 2. Abeta-induced LDLR mis-localization leads to LDLR functional deficits, hyperlipidemia and atherosclerosis. The proposed experiments are significant because they may allow us to conclude that one reason why atherosclerosis, especially in the brain so often accompanies AD is because it is promoted by LDLR functional deficits induced by Abeta. Furthermore, the differences in affinity/activation of the different isoforms of ApoE for LDLR may be made more acute when the LDLR is less active, thus accounting in part for the increased risk of AD imparted by ApoE4. These findings and conclusions form the foundation for a comprehensive series of experiments to test the above hypotheses and determine whether Abeta induces the mis-sorting and functional inactivity of other important neuronal and non-neuronal proteins in the AD, particularly, growth factor receptors and the insulin receptor.