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Journal of Neuroscience, Vol 15, 6239-6249, Copyright © 1995 by Society for Neuroscience
Amyloid beta-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death
RJ Mark, K Hensley, DA Butterfield and MP Mattson
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536, USA.
The amyloid beta-peptide (A beta) 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 A
beta 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 A beta 1-40 or A beta 25-35
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 A beta 25-35 and declined to less
than 40% of basal level by 3 hr. A beta did not impair other
Mg(2+)-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+]i
and neuronal injury. Impairment of Na+/K(+)-ATPase activity appeared to be
causally involved in the elevation of [Ca2+]i and neurotoxicity since
suppression of Na+ influx significantly reduced A beta- and ouabain-induced
[Ca2+]i 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 A beta- induced
impairment of Na+/K(+)-ATPase activity, elevation of [Ca2+]i and
neurotoxicity, suggesting a role for ROS. Finally, exposure of synaptosomes
from postmortem human hippocampus to A beta resulted in a significant and
specific reduction in Na+/K(+)-ATPase and Ca(2+)-ATPase activities, without
affecting other Mg(2+)-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.
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