Calmodulin Prevents the Inhibitory Effect of Neurotoxic β-Amyloid Peptide on Synaptosomal Plasma Membrane Ca2+-ATPase

Abstract

Dysregulation of cellular Ca2+ homeostasis and β-amyloid peptide (Aβ) have been linked to cell dysfunction and death in neurodegenerative disorders, such as Alzheimer's disease (AD). We have recently reported that Ca2+-dependence of plasma membrane Ca2+-ATPase (PMCA) activity is altered in AD-affected brains, and in pig brain in the presence of Aβ fragment (25-35) and full-length Aβ1-40 or 1-42 peptides, being inhibited by those peptides. In the present work, performed with Aβ1-42, we found that Ca2+-calmodulin, the main endogenous activator of PMCA, was able to block the inhibitory effect of Aβ on PMCA activity. Besides, the activity of truncated PMCA mutant lacking the C-terminal domain involved in calmodulin binding was not inhibited by Aβ. Dot blot overlay assays further confirmed an interaction of Aβ peptide with both PMCA and calmodulin. Thus, calmodulin may prevent the inhibitory effect of Aβ on PMCA activity by a mechanism that involves its direct binding to the protein, changing PMCA conformation and thus occluding peptide binding to PMCA, and/or its direct binding to the peptide. These finding may reveal a protection role of calmodulin against the Aβ-induced neurotoxicity in AD.This work was supported by Ministerio de Ciencia e Innovacion (MICINN, project BFU2008-00182), Fundacion Marcelino Botin, Junta de Extremadura and FEDER.