Presenilin-1-deficient neurons are nitric oxide-dependently killed by hydrogen peroxide in vitro

Neuroscience. 2004;125(3):563-8. doi: 10.1016/j.neuroscience.2004.01.016.

Abstract

Presenilin-1 (PS1) is the gene responsible for the development of early-onset familial Alzheimer's disease. To probe the functions of PS1 on neuronal resistance to oxidative stress, we pharmacologically examined the death signals in PS1-deficient neurons induced by oxidative stress. Because the death of primarily cultured neurons lacking PS1 is caused by hydrogen peroxide in calcium-dependent manners in vitro [J Neurochem 78 (2001) 807], we tested the neuronal survival-promoting ability of inhibitors against calcium-dependent/cell death-related signaling molecules, such as ERKs, JNK, p38 MAP kinase, calcineurin, calpain, and nitric oxide synthase (NOS). All inhibitors tested failed to rescue the PS1-deficient neurons from the death with the exception of an inhibitor of NOS, N(G)-nitro-l-arginine methyl ester. Hemoglobin, a nitric oxide (NO) scavenger, also prevented the death of the mutant neurons. NADPH-diaphorase staining, which accounts for NOS activity, was enhanced in the mutant neurons. These results suggest that PS1 has a role for NOS activation in neurons and confers oxidative stress-resistance on neurons in calcium/NO-dependent manners.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / physiopathology
  • Animals
  • Calcium-Binding Proteins / antagonists & inhibitors
  • Calcium-Binding Proteins / metabolism
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Free Radical Scavengers / pharmacology
  • Genetic Predisposition to Disease
  • Hemoglobins / metabolism
  • Hemoglobins / pharmacology
  • Hydrogen Peroxide / toxicity*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Knockout
  • NADPH Dehydrogenase / metabolism
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / physiopathology
  • Neurons / drug effects
  • Neurons / enzymology*
  • Neurons / pathology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism
  • Oxidants / toxicity
  • Oxidative Stress / genetics
  • Presenilin-1

Substances

  • Calcium-Binding Proteins
  • Enzyme Inhibitors
  • Free Radical Scavengers
  • Hemoglobins
  • Membrane Proteins
  • Oxidants
  • Presenilin-1
  • Nitric Oxide
  • Hydrogen Peroxide
  • Nitric Oxide Synthase
  • NADPH Dehydrogenase
  • NG-Nitroarginine Methyl Ester