NEUROTROPHIN REGULATION OF LRP IN CNS NEURONS

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date6/1/985/31/03

Funding

  • National Institute of Neurological Disorders and Stroke: $228,546.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $223,690.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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