LRP in amyloid-β production and metabolism

Guojun Bu, Judy Cam, Celina Zerbinatti

Research output: Chapter in Book/Report/Conference proceedingConference contribution

100 Scopus citations

Abstract

Amyloid-β peptide (Aβ) production and accumulation in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies have shown that apolipoprotein E (apoE) receptors, members of the low-density lipoprotein receptor (LDLR) family, modulate Aβ production as well as Aβ cellular uptake. Aβ is derived from proteolytic processing of the amyloid precursor protein (APP), which interacts with several members of the LDLR family. Studies from our laboratory have focused on two members of the LDLR family, the LDLR-related protein (LRP) and LRP1B. Our in vitro studies have shown that while LRP's rapid endocytosis facilitates APP endocytic trafficking and processing to Aβ, LRP1B's slow endocytosis inhibits these processes. In addition to modulating APP endocytic trafficking, LRP's rapid endocytosis also facilitates Aβ cellular uptake by binding to Aβ either directly or via LRP ligands such as apoE. Our in vivo studies using transgenic mice have shown that overexpression of LRP in central nervous system (CNS) neurons increases soluble brain Aβ and this increase correlates with deficits in memory.Together our studies demonstrate that members of the LDLR family modulate APP processing and Aβ metabolism by several independent mechanisms. Understanding the pathways that modulate brain Aβ metabolismmay enable the rational design of molecular medicine to treat AD.

Original languageEnglish (US)
Title of host publicationIntegrated Molecular Medicine for Neuronal and Neoplastic Disorders
PublisherBlackwell Publishing Inc.
Pages35-53
Number of pages19
ISBN (Print)1573316555, 9781573316552
DOIs
StatePublished - Nov 2006

Publication series

NameAnnals of the New York Academy of Sciences
Volume1086
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • APP
  • Alzheimer's disease
  • LDL receptor
  • LRP
  • LRP1B

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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