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

María Berrocal^*, Daniel Marcos^*, M. Rosario Sepúlveda^*, Mar Pérez, Jesús Ávila and Ana M. Mata^*,1

^* Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain; and

Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain

¹Correspondence: Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Avda de Elvas s/n, 06071 Badajoz, Spain. E-mail: anam{at}unex.es

High-affinity Ca²⁺ transport ATPases play a crucial role in controlling cytosolic Ca²⁺. The amyloid β-peptide (Aβ) 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 Aβ 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 Aβ to AD brain has no effect on PMCA activity. Aβ also decreases the activity of PMCA purified from pig cerebrum, the effect being isoform specific. The level of inhibition of purified PMCA caused by Aβ is reduced by cholesterol, and the level of inhibition of PMCA activity by Aβ in the raft fraction of pig synaptosomal membranes is lower than for the nonraft fraction. We conclude that the effect of Aβ 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., Sepúlveda, M. R., Pérez, M., Ávila, J., Mata, A. M. Altered Ca²⁺ dependence of synaptosomal plasma membrane Ca²⁺-ATPase in human brain affected by Alzheimer’s disease.

Key Words: neurodegeneration • amyloid β-peptide • postmortem • activity