Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders.

Abstract

Calcium signalling in astrocytes is a fundamental mechanism for maintaining brain homeostasis, shaping neuronal activity, and coordinating vascular and immune responses. Once considered secondary to neuronal signalling, astrocytic Ca²⁺ dynamics are now recognized as highly versatile, spatially compartmentalized and essential for regulating neurotransmitter uptake, ion buffering, metabolic support and mitochondrial function. Accumulating evidence shows that these Ca²⁺ signalling pathways are progressively remodelled during ageing and become profoundly dysregulated in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis. Importantly, astrocyte Ca²⁺ alterations are heterogeneous and context-dependent, ranging from aberrant spontaneous activity to loss of signalling in specific subcellular domains, reflecting the disease stage, brain region and molecular pathology. Disruption of astrocyte Ca²⁺ homeostasis compromises core homeostatic functions and contributes to neuronal vulnerability, circuit dysfunction and impaired neurovascular regulation. By integrating current evidence across physiological, ageing and disease contexts, this Review highlights astrocytic Ca²⁺ signalling as a central node in neurodegenerative pathophysiology and underscores its potential as a target for therapeutic intervention.