Aberrant subcellular neuronal calcium regulation in aging and Alzheimer's disease

► During aging brain cells are subjected to elevated levels of oxidative and metabolic stress which may perturb cellular calcium homeostasis in ways that render neurons vulnerable to synaptic dysfunction, degeneration and cell death. ► In Alzheimer's disease, aberrant proteolytic processing of the β-amyloid precursor protein results in excessive production and self-aggregation of the amyloid β-peptide which can generate reactive oxygen species resulting in impairment of membrane ion-motive ATPases and glutamate and glucose transporters thereby contributing to cellular calcium overload and energy failure. ► Mutations in presenilin-1 that cause many cases of early-onset inherited Alzheimer's disease alter calcium regulation in the endoplasmic reticulum, which may contribute to synaptic damage and neuronal degeneration. ► By activating adaptive cellular stress response pathways involving neurotrophic factors, protein chaperones and antioxidant systems, exercise, dietary energy restriction and cognitive enrichment may stabilize cellular calcium homeostasis and protect the brain against aging and Alzheimer's disease. ► Pharmacological interventions that protect neurons against cellular calcium overload may prove beneficial in delaying the onset and slowing the progression of cognitive impairment in aging and Alzheimer's disease.