Astroglial Calcium Signaling in Aging and Alzheimer's Disease

Astrocytes are the homeostatic and protective cells of the central nervous system (CNS). In neurological diseases, astrocytes undergo complex changes, which are subclassified into (1) reactive astrogliosis, an evolutionary conserved defensive rearrangement of cellular phenotype aimed at neuroprotection; (2) pathological remodeling, when astrocytes acquire new features driving pathology; and (3) astrodegeneration, which is manifested by astroglial atrophy and loss of homeostatic functions. In aging brains as well as in the brains affected by Alzheimer's disease (AD), astrocytes acquire both atrophic and reactive phenotypes in a region- and disease-stage-dependent manner. Prevalence of atrophy overreactivity, observed in certain brain regions and in terminal stages of the disease, arguably facilitates the development of neurological deficits. Astrocytes exhibit ionic excitability mediated by changes in intracellular concentration of ions, most importantly of Ca²⁺ and Na⁺, with intracellular ion dynamics triggered by the activity of neural networks. AD astrocytes associated with senile plaques demonstrate Ca²⁺ hyperactivity in the form of aberrant Ca²⁺ oscillations and pathological long-range Ca²⁺ waves. Astroglial Ca²⁺ signaling originating from Ca²⁺ release from the endoplasmic reticulum is a key factor in initiating astrogliotic response; deficient Ca²⁺ signaling toolkits observed in entorhinal and prefrontal cortices of AD model animals may account for vulnerability of these regions to the pathology.