Altered Ca ²⁺ dependence of synaptosomal plasma membrane Ca ²⁺ ‐ATPase in human brain affected by Alzheimer's disease

Abstract

High-affinity Ca(2+) transport ATPases play a crucial role in controlling cytosolic Ca(2+). The amyloid beta-peptide (Abeta) is a neurotoxic agent found in affected neurons in Alzheimer's disease (AD) that has been implicated in dysregulation of Ca(2+) homeostasis. Using kinetic assays, we have shown that the Ca(2+) dependencies of intracellular Ca(2+)-ATPase (SERCA and SPCA) activity are the same in human AD and normal brain but that of plasma membrane Ca(2+)-ATPase (PMCA) is different. The addition of Abeta to normal brain decreases the PMCA activity measured at pCa 5.5, resulting in the same Ca(2+)dependency as that seen in AD brain, whereas the addition of Abeta to AD brain has no effect on PMCA activity. Abeta also decreases the activity of PMCA purified from pig cerebrum, the effect being isoform specific. The level of inhibition of purified PMCA caused by Abeta is reduced by cholesterol, and the level of inhibition of PMCA activity by Abeta in the raft fraction of pig synaptosomal membranes is lower than for the nonraft fraction. We conclude that the effect of Abeta on PMCA activity could be important in amyloid toxicity, resulting in cytoplasmic Ca(2+) dysregulation and could explain the different Ca(2+) dependencies of PMCA activity observed in normal and AD brain.

Plasma membrane Ca2+-ATPases: Targets of oxidative stress in brain aging and neurodegeneration

“…PMCA activity in human brain tissue from Alzheimer's disease patients shows an altered dependence on Ca 2+ compared to control brain with stimulation of activity at lower concentrations and less inhibition at high Ca 2+ concentrations [100] suggesting that the affinity of the stimulatory site for Ca 2+ increases and that for the inhibitory site decreases in Alzheimer's brain. More interestingly, addition of amyloid beta peptide to control brain altered its Ca 2+ dependency to resemble that of Alzheimer' s disease brain [100] . In preliminary studies on human brain tissue from Parkinson's disease, we have observed a significant reduction in PMCA activity compared to agematched controls [101] .…”

“…The relationship between the PMCAs and Alzheimer's disease, the most common age-dependent neurodegenerative disorder, was first suggested by a reduction in PMCA activity in neurons exposed to the amyloid beta peptide [97][98][99] . Recent studies have further established the involvement of the PMCA in Alzheimer's disease [100] . PMCA activity in human brain tissue from Alzheimer's disease patients shows an altered dependence on Ca 2+ compared to control brain with stimulation of activity at lower concentrations and less inhibition at high Ca 2+ concentrations [100] suggesting that the affinity of the stimulatory site for Ca 2+ increases and that for the inhibitory site decreases in Alzheimer's brain.…”

“…Recent studies have further established the involvement of the PMCA in Alzheimer's disease [100] . PMCA activity in human brain tissue from Alzheimer's disease patients shows an altered dependence on Ca 2+ compared to control brain with stimulation of activity at lower concentrations and less inhibition at high Ca 2+ concentrations [100] suggesting that the affinity of the stimulatory site for Ca 2+ increases and that for the inhibitory site decreases in Alzheimer's brain. More interestingly, addition of amyloid beta peptide to control brain altered its Ca 2+ dependency to resemble that of Alzheimer' s disease brain [100] .…”

Combined arsenic and di-(2-ethylhexyl) phthalate exposure elicits responses in brain ATPases different from hepatic and renal activities in rats

“…Increased ATPase activities have been associated with a number of pathological states including autism, Alzheimer's disease, Parkinson syndrome, Cushing's syndrome (Berrocal et al, 2009;Ji et al, 2000;Wambach et al, 1980). Brain-region specific increases in the activities of Na + /K + ATPase and Ca 2+ Mg 2+ ATPase have also been reported in neurodisorders such as autism and Alzheimer disease.…”

An improved method for expression and purification of functional human Ca2+ transporter PMCA4b in Saccharomyces cerevisiae

“…Complex alternative splicing processes at a site in the first cytosolic loop of the pump, and within the C-terminal calmodulin-binding domain, generate numerous pump variants with special properties. Our group has been studying PMCAs, with a special interest in PMCA4 because this isoform is quite abundant in brain [10] and functional inhibition, loss, mutation or inefficient expression of specific PMCA4 isoforms are associated to different pathologies including several neuropathies [10,11]. In fact, this isoform seems to be functionally inhibited by molecular markers of Alzheimer disease (AD), such as amyloid b-peptide (Ab) and tau [10,12].…”