Calcium in the initiation, progression and as an effector of Alzheimer’s disease pathology

Abstract•  Introduction ‐  Familial and sporadic AD ‐  APP processing and the amyloid cascade hypothesis•  Calcium in the initiation of pathology ‐  Effects of calcium on APP processing and Aβ deposition/aggregation ‐  Genetic linkage in calcium related genes and AD ‐  Apoε4 and calcium ‐  Calcium and APP processing ‐  Synaptic regulation of Aβ production‐  Normal age‐related changes in calcium homeostasis and AD pathology ‐  Age‐related reductions in autophagy•  Calcium in disease progression ‐  Linking Aβ and τ ‐  Calcium, calpains and τ pathology•  Calcium as a disease effector ‐  Synaptic calcium dyshomeostasis and AD – a focus on    NMDA receptors ‐  Aβ elevates cytosolic intracellular calcium    levels in vivo‐  Aβ and mitochondrial calcium dyshomeostasis•  Current therapeutics •  ConclusionsThe cause(s) of sporadic Alzheimer’s disease (sAD) are complex and currently poorly understood. They likely result from a combination of genetic, environmental, proteomic and lipidomic factors that crucially occur only in the aged brain. Age‐related changes in calcium levels and dynamics have the potential to increase the production and accumulation of both amyloid‐β peptide (Aβ) and τ pathologies in the AD brain, although these two pathologies themselves can induce calcium dyshomeostasis, particularly at synaptic membranes. This review discuses the evidence for a role for calcium dyshomeostasis in the initiation of pathology, as well as the evidence for these pathologies themselves disrupting normal calcium homeostasis, which lead to synaptic and neuronal dysfunction, synaptotoxicity and neuronal loss, underlying the dementia associated with the disease.