AMYLOID BETA-PEPTIDE IMPAIRS ION-MOTIVE ATPASE ACTIVITIES - EVIDENCE FOR A ROLE IN LOSS OF NEURONAL CA2-DEATH( HOMEOSTASIS AND CELL)

The amyloid beta-peptide (A beta) that accumulates as insoluble plaque s in the brain in Alzheimer's disease can be directly neurotoxic and c an increase neuronal vulnerability to excitotoxic insults. The mechani sm 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 ac tivity which precedes loss of calcium homeostasis and cell degeneratio n, Na+/K+-ATPase activity was reduced within 30 min of exposure to A b eta 25-35 and declined to less than 40% of basal level by 3 hr. A beta did not impair other Mg2+-dependent ATPase activities or Na+/Ca2+ exc hange. Experiments with ouabain, a specific inhibitor of the Na+/K+-AT Pase, demonstrated that impairment of this enzyme was sufficient to in duce an elevation of [Ca2+](i) and neuronal injury. Impairment of Na+/ K+-ATPase activity appeared to be causally involved in the elevation o f [Ca2+](i) and neurotoxicity since suppression of Na+ influx signific antly reduced A beta- and ouabain-induced [Ca2+](i) elevation and neur onal death. Neuronal degeneration induced by ouabain appeared to be of an apoptotic form as indicated by nuclear condensation and DNA fragme ntation. The antioxidant free radical scavengers vitamin E and propylg allate significantly attenuated A beta-induced impairment of Na+/K+-AT Pase 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 Ca2+-ATPase activities, without affecting other Mg2+-dependent ATPase activities or Na+/Ca2+ exchange. These data sugg est that impairment of ion-motive ATPases may play a role in the patho genesis of neuronal injury in Alzheimer's disease.