Superoxide mediates the cell-death-enhancing action of presenilin-1 mutations

J Neurosci Res. 1999 Jun 1;56(5):457-70. doi: 10.1002/(SICI)1097-4547(19990601)56:5<457::AID-JNR2>3.0.CO;2-P.

Abstract

The mechanism whereby mutations in the presenilin-1 (PS-1) gene on chromosome 14 cause early-onset inherited Alzheimer's disease are unknown. We report that PC6 neural cells (a subclone of PC12 cells) expressing PS-1 mutations (M146V and L286V) exhibit increased superoxide production, nitrotyrosine accumulation, and membrane lipid peroxidation following exposure to amyloid beta-peptide 1-42 (Abeta). Mitochondrial calcium accumulation and membrane depolarization following exposure to Abeta were enhanced in cells expressing mutant PS-1. Overexpression of mitochondrial Mn-SOD greatly reduced superoxide production, nitrotyrosine formation, membrane lipid peroxidation, intramitochondrial calcium accumulation, and membrane depolarization following exposure to Abeta and conferred resistance to the apoptosis-enhancing action of the PS-1 mutations. Nitric oxide synthase inhibitors and the peroxynitrite scavenger uric acid blocked the apoptosis-enhancing action of PS-1 mutations. The data suggest pivotal roles for superoxide production and resulting peroxynitrite formation in the pathogenic mechanism of PS-1 mutations.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / genetics
  • Amino Acid Substitution
  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Calcium / metabolism
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Chromosomes, Human, Pair 14
  • Humans
  • Intracellular Membranes / physiology
  • Lipid Peroxidation / drug effects
  • Membrane Lipids / metabolism
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / physiology
  • Mutagenesis, Site-Directed
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • PC12 Cells
  • Peptide Fragments / pharmacology*
  • Presenilin-1
  • Rats
  • Reactive Oxygen Species / metabolism
  • Recombinant Proteins / metabolism
  • Superoxide Dismutase / metabolism
  • Superoxides / metabolism*
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Amyloid beta-Peptides
  • Membrane Lipids
  • Membrane Proteins
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • Reactive Oxygen Species
  • Recombinant Proteins
  • amyloid beta-protein (1-42)
  • Superoxides
  • 3-nitrotyrosine
  • Tyrosine
  • Superoxide Dismutase
  • Calcium