Calcium Signaling Regulated by Cellular Membrane Systems and Calcium Homeostasis Perturbed in Alzheimer's Disease.

Although anything that changes spatiotemporally could be a signal, cells, particularly neurons, precisely manipulate calcium ion (Ca) to transmit information. Ca homeostasis is indispensable for neuronal functions and survival. The cytosolic Ca concentration ([Ca]) is regulated by channels, pumps, and exchangers on cellular membrane systems. Under physiological conditions, both endoplasmic reticulum (ER) and mitochondria function as intracellular Ca buffers. Furthermore, efficient and effective Ca flux is observed at the ER-mitochondria membrane contact site (ERMCS), an intracellular membrane juxtaposition, where Ca is released from the ER followed by mitochondrial Ca uptake in sequence. Hence, the ER intraluminal Ca concentration ([Ca]), the mitochondrial matrix Ca concentration ([Ca]), and the [Ca] are related to each other. Ca signaling dysregulation and Ca dyshomeostasis are associated with Alzheimer's disease (AD), an irreversible neurodegenerative disease. The present review summarizes the cellular and molecular mechanism underlying Ca signaling regulation and Ca homeostasis maintenance at ER and mitochondria levels, focusing on AD. Integrating the amyloid hypothesis and the calcium hypothesis of AD may further our understanding of pathogenesis in neurodegeneration, provide therapeutic targets for chronic neurodegenerative disease in the central nervous system.