Amyloid beta-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death

Abstract

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.

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

“…The reported decrease in glucose uptake mediated by stress or by high levels of GCs could place neurons in an energy-compromised environment, which could detrimentally affect neuronal responsiveness to pathophysiological events. In fact, glucose transport impairment precedes ATP depletion in brain, increasing neuronal vulnerability to excitotoxicity by compromising function of ion-motive ATPases (Mark et al, 1995), as it has been seen to occur in some neurodegenerative processes such Ab-induced toxicity, schizophrenia and others (Novelli et al, 1988;Kalaria and Harik, 1989;Sims, 1990;Mark et al, 1997;McDermott and De Silva, 2005) in which the reduction in glucose uptake occurs as an early step in the disease process prior to neuronal degeneration (Pettegrew et al, 1994;Reiman et al, 1996). On the other hand, GCs promote reduction in ATP levels (Tombaugh and Sapolsky, 1992;Lawrence and Sapolsky, 1994).…”

Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

“…Sulfhydryl groups in membrane Ca 2ϩ pumps are characteristic targets of oxidative injury (Rohn et al, 1993), and damage to these structures by A␤ has been documented (Mark et al, 1995). It has been proposed that Ca 2ϩ plays an important role in A␤-mediated cell death (Mattson, 1994).…”

“…The mechanism of toxicity is not totally understood. In addition to free radicals, increased sensitivity to excitotoxicity (Copani et al, 1995) and /or disruption of Ca 2ϩ homeostasis (Mattson et al, 1992(Mattson et al, , 1993Le et al, 1995;Mark et al, 1995) seem to be involved. The magnitude of the damage contributed by each of these factors and the extent of their interaction are unresolved issues (Busciglio et al, 1993;Mattson, 1994;Weiss et al, 1994;Copani et al, 1995).…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Neuronal iron deposition causes oxidative stress via the Fenton reaction, which might contribute to elevated oxidative stress observed in the AD brain [109]. Iron-induced oxidative stress has been shown to initiate several apoptotic signaling pathways in neurons [110], and damage proteins such as Ca 2+ -ATPase [111][112][113][114], glutamate transporter [115][116][117], apolipoprotein E [118,119], and Na + /K + -ATPase [111,114,120,121], as well as N-methyl-D-aspartate (NMDA) receptor [122][123][124], and lipids such as cholesterol [125][126][127], ceramides [128,129], and unsaturated fatty acids [130][131][132][133], as well as sphingomyelin [134,135]. Oxidative damage to proteins and lipids by iron can cause synaptic dysfunction and neuronal cell death [136].…”