Significance: Numerous cellular processes and signaling mechanisms have been identified that contribute to Alzheimer's disease (AD) pathology; however, a comprehensive or unifying pathway that binds together the major disease features remains elusive. As an upstream mechanism, altered calcium (Ca²⁺) signaling is a common driving force for many pathophysiological events that emerge during normal aging and development of neurodegenerative disease.

Recent Advances: Over the previous three decades, accumulated evidence has validated the concept that intracellular Ca²⁺ dysregulation is centrally involved in AD pathogenesis, including the aggregation of pathogenic β-amyloid (Aβ) and phospho-τ species, synapse loss and dysfunction, cognitive impairment, and neurotoxicity.

Critical Issues: Although neuronal Ca²⁺ signaling within the cytosol and endoplasmic reticulum (ER) has been well studied, other critical central nervous system-resident cell types affected by aberrant Ca²⁺ signaling, such as astrocytes and microglia, have not been considered as thoroughly. In addition, certain intracellular Ca²⁺-harboring organelles have been well studied, such as the ER and mitochondria; however other critical Ca²⁺-regulated organelles, such as lysosomes and autophagosomes, have only more recently been investigated. In this review, we examine Ca²⁺ dysregulation in microglia and astrocytes, as well as key intracellular organelles important for cellular maintenance and protein handling. Ca²⁺ dysregulation within these non-neuronal cells and organelles is hypothesized to disrupt the effective clearance of misaggregated proteins and cellular signaling pathways needed for memory networks.

Future Directions: Overall, we aim to explore how these disrupted mechanisms could be involved in AD pathology and consider their role as potential therapeutic targets. Antioxid. Redox Signal. 29, 1158–1175.