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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 significant challenge to global healthcare systems, with an exacerbation by an aging population. Although the plethora of hypotheses are proposed to elucidate the underlying mechanisms of AD, from amyloid-beta (Aβ) accumulation and Tau protein aggregation to neuroinflammation, a comprehensive understanding of its pathogenesis remains elusive. Recent research has highlighted the critical role of calcium (Ca 2+ ) signaling pathway in the progression of AD, indicating a complex interplay between Ca 2+ dysregulation and various pathological processes. This review aims to consolidate the current understanding of the role of Ca 2+ signaling dysregulation in AD, thus emphasizing its central role amidst various pathological hypotheses. We aim to evaluate the potential of the Ca 2+ signaling hypothesis to unify existing theories of AD pathogenesis and explore its implications for developing innovative therapeutic strategies through targeting Ca 2+ dysregulation. The review focuses on three principal concepts. First, the indispensable role of Ca 2+ homeostasis in neuronal function and its disruption in AD. Second, the interaction between Ca 2+ signaling dysfunction and established AD hypotheses posited that Ca 2+ dysregulation is a unifying pathway. Third, the dual role of Ca 2+ in neurodegeneration and neuroprotection, highlighting the nuanced effects of Ca 2+ levels on AD pathology.
Wang et al. (Wed,) studied this question.