The molecular link between beta- and gamma-secretase activity on the amyloid beta precursor protein

Cell Mol Life Sci. 2007 Sep;64(17):2211-8. doi: 10.1007/s00018-007-7219-3.

Abstract

Alzheimer's disease (AD) is characterized by an accumulation in the brain of amyloid beta peptides (Abeta). The production of Abeta requires two sequential cleavages induced by beta- and gamma-secretases on the beta-amyloid precursor protein (APP). Altered activity of these secretases is involved in the pathogenesis of AD. The expression and activity of beta-secretase (BACE1) is augmented in the brain in late-onset sporadic AD. Mutant presenilin 1 (PS1), the major genetic defect of early-onset familial AD (FAD), alters the activity of gamma-secretase, leading to increased production of Abeta42. Here we review the role of oxidative stress as a molecular link between the beta- and the gamma-secretase activities, and provide a mechanistic explanation of the pathogenesis of sporadic late-onset AD. We also discuss evidence for a role of the same mechanism in the pathogenesis of familial AD carrying PS1 mutations.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / enzymology*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid Precursor Protein Secretases / physiology
  • Amyloid beta-Protein Precursor / metabolism*
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / physiology
  • Humans
  • Oxidative Stress / physiology*
  • Presenilins / genetics

Substances

  • Amyloid beta-Protein Precursor
  • Presenilins
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human