Network-wide dysregulation of calcium homeostasis in Alzheimer’s disease

Dysregulation of intracellular Ca²⁺ homeostasis has been proposed as a common proximal cause of neural dysfunction during aging and Alzheimer’s disease (AD). In this context, aberrant Ca²⁺ signaling has been viewed as a neuronal phenomenon mostly related to the dysfunction of intracellular Ca²⁺ stores. However, recent data suggest that, in AD, Ca²⁺ dyshomeostasis is not restricted to neurons but represents a global phenomenon affecting virtually all cells in the brain. AD-related aberrant Ca²⁺ signaling in astrocytes and microglia, which is activated during the disease, probably contributes profoundly to an inflammatory response that, in turn, impacts neuronal Ca²⁺ homeostasis and brain function. Based on recent data obtained in vivo and in vitro, we propose that bidirectional interactions between the inflammatory responses of glial cells and aberrant Ca²⁺ signaling represent a vicious cycle accelerating disease progression.