The low density lipoprotein receptor-related protein (LRP) is a multifunctional endocytic receptor that is expressed abundantly in neurons of the central nervous system (CNS). Two LRP ligands, apolipoprotein E (apoE)/lipoprotein and beta-amyloid precursor protein (APP), have been shown genetically to play important roles in the pathogenesis of Alzheimer s disease (AD). While mutations in the APP gene cause certain forms of early-onset familial AD, the presence of the xi4 allele of apoE is a risk factor for both familial and sporadic late- onset AD. In addition to its role in the catabolism of its ligands, LRP itself has been identified as a component of senile plaques, a pathological hallmark of AD. We hypothesize that regulation of LRP expression and function in CNS neurons can directly influence the catabolism and functions of apoE/lipoprotein, APP, and beta-amyloid peptide (Abeta), and thereby impact on AD pathogenesis. Over the past few years, we have systematically examined the expression, endocytic function, and the biogenesis of LRP in various cells derived from the CNS. We have shown that normal development of hippocampal neuronal structure in vitro requires functional LRP on the cell surface, and that LRP mediates differential effects of apoE isoforms on neurite outgrowth. Interestingly, our most recent results indicate that cell surface LRP in specific neuronal cell lines can be rapidly up-regulated (over minutes) by nerve growth factor (NGF). To our knowledge, this is the first example in which a neurotrophic factor has been shown to rapidly alter the cellular distribution of an endocytic receptor. The long term goals of this proposal are to elucidate the molecular mechanisms by which LRP is regulated in neuronal systems, the consequences of LRP regulation, and the role of LRP in the pathogenesis of AD. Thus, we propose the following specific aims: 1) to examine the regulation of LRP expression by neurotrophins in primary cultures of CNS neurons; 2) to investigate which intracellular signaling pathway activated by neurotrophins is responsible for LRP up-regulation; 3) to identify the cis-elements within the LRP tail and/or the endosomal component that responds to the neurotrophin signal; and 4) to analyze whether neurotrophin regulation of LRP influences the processing of APP and the catabolism of Abeta. Results from these studies should not only enhance our understanding about the functions of LRP in the CNS, but also provide strategies as to how this receptor and its ligands can be regulated in vivo under pathophysiological conditions.
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