Although the calcium-sensing receptor (CaSR) is expressed by all types of nerve cells in widespread areas of the human central nervous system (CNS), so far its roles in brain pathophysiology remain largely unknown. Here, we review the available evidence concerning the stages of development of sporadic late-onset Alzheimer's disease (LOAD) and the roles therein played by CaSR signaling. As the brain ages, its ability to dispose of dangerous synapse-targeting soluble amyloid beta-(1-42) (sA beta 42) oligomers released from normal neuronal activity declines. As their levels slowly rise, these oligomers increasingly target and eliminate synapses and prevent synapse formation, thereby eroding the foundations of memory formation and cognitive functions. In this initial stage, neurons, even though synaptically impaired, remain alive. Concurrently, sA beta 42 oligomers by binding to CaSR on human astrocytes induce via mitogen activated protein kinase (MAPK) activity the release of huge amounts nitric oxide (NO), which by itself and after conversion to peroxynitrite (ONOO-) damages neighboring neurons. When the sA beta 42 oligomers increasingly aggregate into fibrillar plaques, they attract and activate microglial macrophages that, while trying to clear the plaques, produce via A beta-activated CaSR signaling several proinflammatory cytokines and reactive oxygen species (ROS). Notably, the microglial cytokines, like sA beta 42 oligomers, induce human astrocytes to make large amounts of NO and hence ONOO- via CaSR signal-dependent MAPK activity. The microglial cytokines-activated astrocytes might also produce their own sA beta 42, which would combine with neuron- and microglia-released sA beta 42 to increase the fibrillar burden and promote the further production of reactive oxygen species (ROS), NO/ONOO-, and proinflammatory cytokines to efficiently kill both normal and functionally impaired (undead) neurons. But, on a somewhat positive note, we speculate that the astrocytes' CaSR-stimulated MAPK activities might also induce vascular endothelial growth factor (VEGF) expression and production. This might in turn enhance neuronal stem cells neurogenesis at least in the subgranular zone (SGZ) of the hippocampal dentate gyrus.
