Elucidation of Ca2+ Influx through Alzheimer's Aβ Channels in the Aβ-Induced Cellular Ca2+ Response

Abstract

The Alzheimer's disease Aβ peptide interaction with the plasma membrane of cells results in a response characterized by the elevation of the intracellular (cytoplasmic) Ca2+ concentration which may critically perturb Ca2+ homeostasis. Calcium influx into the cytosol can occur across the plasma membrane via receptor-mediated, voltage-gated, store-operated calcium channels, or from internal stores. Based on the ion channel formation by Aβ peptides on artificial membranes we have proposed that perturbation in Ca2+ homeostasis induced by Aβ could be caused by external calcium entering through ion channels formed by Aβ in the plasma membrane. The activity of these channels would permit the entrance of extracellular calcium ions into the cell, subsequently triggering the release of calcium from internal stores. To elucidate the contribution of calcium influx through the Aβ ion channels to the Aβ-induced calcium response we used specific blockers of plasma membrane channels and specific inhibitors of the mechanisms that permit the release of calcium from the ER, the largest intracellular store. With all those mechanisms blocked and inhibited, we visualized a fast raising, short-lasting calcium entry immediately after PC12 cells were exposed to Aβ. This calcium signal was identified as calcium flowing through the Aβ channels by using specific Aβ channel blockers. The Aβ channel blockers did not affect other mechanisms that contribute to the cytosolic calcium increase, and their use prevented the calcium entry through the Aβ channels and consequent development of the whole cellular Aβ-induced calcium response.