Calcium Signaling Deficits in Glia and Autophagic Pathways Contributing to Neurodegenerative Disease

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.

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.

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.