Calcium signaling hypothesis: A non-negligible pathogenesis in Alzheimer’s disease

作者：Minghui Wang, Hu Zhang, Jiling Liang, Jielun Huang, Tong Wu, Ning Chen · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.01.007 · 被引用次数：18 · 研究领域：Alzheimer's disease research and treatments、Endoplasmic Reticulum Stress and Disease、Nuclear Receptors and Signaling

The interplay between the Ca 2+ signaling hypothesis and the pathogenesis of AD. The amyloid cascade hypothesis, Tau protein hypothesis, mitochondrial dysfunction hypothesis, neuroinflammation hypothesis, and autophagy dysfunction hypothesis, among others, collectively contribute to the onset and progression of AD through their impact on Ca 2+ transport and Ca 2+ signaling pathways. • Disrupted calcium homeostasis serves as the pathological foundation underlying various hypotheses of AD. • The calcium signaling hypothesis is primarily defined by the overactivation of calcium signals, stemming from an elevated intracellular calcium concentration. • Abnormal calcium signaling and levels are crucial in the pathogenesis of AD, not only influencing the production and aggregation of Aβ peptides but also through the calcium/calpain signaling pathway, which is instrumental in regulating the phosphorylation of Tau protein. • Mitochondrial calcium overload contributes to metabolic disorders and oxidative stress in AD by impairing oxidative phosphorylation and increasing electron leakage in the electron transport chain. • Calcium signaling within microglia and astrocytes, along with their interactions with neurons, plays a pivotal role in the neuroinflammatory processes associated with AD. • Abnormal calcium signaling leads to autophagy dysfunction, characterized by the inhibition of autophagosome formation and impaired lysosomal acidification. Alzheimer’s disease (AD) presents a signif...