Altered Ca2+ dependence of synaptosomal plasma membrane Ca2+-ATPase in human brain affected by Alzheimer's disease

High-affinity Ca2+ transport ATPases play a crucial role in controlling cytosolic Ca2+. The amyloid beta-peptide (A beta) is a neurotoxic agent found in affected neurons in Alzheimer's disease (AD) that has been implicated in dysregulation of Ca2+ homeostasis. Using kinetic assays, we have shown that the Ca2+ dependencies of intracellular Ca2+-ATPase (SERCA and SPCA) activity are the same in human AD and normal brain but that of plasma membrane Ca2+-ATPase (PMCA) is different. The addition of A beta to normal brain decreases the PMCA activity measured at pCa 5.5, resulting in the same Ca2+ dependency as that seen in AD brain, whereas the addition of A beta to AD brain has no effect on PMCA activity. A beta also decreases the activity of PMCA purified from pig cerebrum, the effect being isoform specific. The level of inhibition of purified PMCA caused by A beta is reduced by cholesterol, and the level of inhibition of PMCA activity by A beta in the raft fraction of pig synaptosomal membranes is lower than for the nonraft fraction. We conclude that the effect of A beta on PMCA activity could be important in amyloid toxicity, resulting in cytoplasmic Ca2+ dysregulation and could explain the different Ca2+ dependencies of PMCA activity observed in normal and AD brain.-Berrocal, M., Marcos, D., Sepulveda, M. R., Perez, M., A Avila, J., Mata, A. M. Altered Ca2+ dependence of synaptosomal plasma membrane Ca2+-ATPase in human brain affected by Alzheimer's disease. FASEB J. 23, 1826-1834 (2009)