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 (Ca²⁺) to transmit information. Ca²⁺ homeostasis is indispensable for neuronal functions and survival. The cytosolic Ca²⁺ concentration ([Ca²⁺]_CYT) is regulated by channels, pumps, and exchangers on cellular membrane systems. Under physiological conditions, both endoplasmic reticulum (ER) and mitochondria function as intracellular Ca²⁺ buffers. Furthermore, efficient and effective Ca²⁺ flux is observed at the ER-mitochondria membrane contact site (ERMCS), an intracellular membrane juxtaposition, where Ca²⁺ is released from the ER followed by mitochondrial Ca²⁺ uptake in sequence. Hence, the ER intraluminal Ca²⁺ concentration ([Ca²⁺]_ER), the mitochondrial matrix Ca²⁺ concentration ([Ca²⁺]_MT), and the [Ca²⁺]_CYT are related to each other. Ca²⁺ signaling dysregulation and Ca²⁺ dyshomeostasis are associated with Alzheimer's disease (AD), an irreversible neurodegenerative disease. The present review summarizes the cellular and molecular mechanism underlying Ca²⁺ signaling regulation and Ca²⁺ 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.