β-Secretase Processing of the Alzheimer's Amyloid Protein Precursor (APP)

Laura Marlow, Melissa Cain, Miguel A. Pappolla, Kumar Sambamurti

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

An integral membrane aspartyl protease, BACE, is responsible for β-secretase processing of the β-amyloid precursor protein (APP) to the large secreted sAPPβ and membrane-bound CTFβ of 99 residues. CTFβ is subsequently cleaved within the membrane by γ-secretase to the amyloid β protein (Aβ) that is deposited in the Alzheimer's disease (AD) brain. In this manuscript, we argue that BACE is not limiting for Aβ production and report the existence of a high molecular weight complex of BACE that is more active than the monomer. We also present evidence that the BACE complex is enriched in lipid raft fractions prepared from brain membranes. These findings support the hypothesis that cleavage by BACE is limited by trafficking of APP (<10%) to a lipid raft-derived compartment containing the BACE complex. In addition, the localization of the BACE complex to lipid rafts can explain previous findings that cholesterol and glycosylphosphatidylinositol (GPI)-anchored proteins are necessary for β-secretase processing of APP. We propose that the BACE complex is a better drug target than the monomer for specific inhibition of Aβ biogenesis.

Original languageEnglish (US)
Pages (from-to)233-239
Number of pages7
JournalJournal of Molecular Neuroscience
Volume20
Issue number3
DOIs
StatePublished - Dec 1 2003
Externally publishedYes

Keywords

  • Amyloid
  • Aspartyl protease
  • BACE1
  • Memapsin-2
  • Trafficking

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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