Abstract
The amyloid β-peptide (Aβ) that accumulates as insoluble plaques in the brain in Alzheimer's disease can be directly neurotoxic and can increase neuronal vulnerability to excitotoxic insults. The mechanism of Aβ toxicity is unclear but is believed to involve generation of reactive oxygen species (ROS) and loss of calcium homeostasis. We now report that exposure of cultured rat hippocampal neurons to Aβ1-40 or Aβ25-35 causes a selective reduction in Na+/ K+-ATPase activity which precedes loss of calcium homeostasis and cell degeneration. Na+/K+-ATPase activity was reduced within 30 min of exposure to Aβ25-35 and declined to less than 40% of basal level by 3 hr. Aβ did not impair other Mg2+-dependent ATPase activities or Na+/Ca2+ exchange. Experiments with ouabain, a specific inhibitor of the Na+/K+-ATPase, demonstrated that impairment of this enzyme was sufficient to induce an elevation of [Ca2+], and neuronal injury. Impairment of Na+/K+-ATPase activity appeared to be causally involved in the elevation of [Ca2+], and neurotoxicity since suppression of Na+ influx significantly reduced Aβ- and ouabain-induced [Ca2+], elevation and neuronal death. Neuronal degeneration induced by ouabain appeared to be of an apoptotic form as indicated by nuclear condensation and DNA fragmentation. The antioxidant free radical scavengers vitamin E and propylgallate significantly attenuated Aβ-induced impairment of Na+/ K+-ATPase activity, elevation of [Ca2+], and neurotoxicity, suggesting a role for ROS. Finally, exposure of synaptosomes from postmortem human hippocampus to Aβ resulted in a significant and specific reduction in Na+/K+-ATPase and Ca2+-ATPase activities, without affecting other Mg2+ -dependent ATPase activities or Na+/Ca2+ exchange. These data suggest that impairment of ion-motive ATPases may play a role in the pathogenesis of neuronal injury in Alzheimer's disease.
Original language | English (US) |
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Pages (from-to) | 6239-6249 |
Number of pages | 11 |
Journal | Journal of Neuroscience |
Volume | 15 |
Issue number | 9 |
State | Published - Sep 1995 |
Externally published | Yes |
Keywords
- Alzheimer's disease
- Antioxidants
- Calcium-ATPase
- Free radicals
- Hippocampus
- Na/K-ATPase
- Ouabain
- Reactive oxygen species
- Sodium-calcium exchange
- Synaptic membrane
ASJC Scopus subject areas
- General Neuroscience