摘要Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This review presents a brief background of the development of novel concepts and their clinical potentials.The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca2+influx is critical for neuronal function.An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca2+mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic site.This Ca2+-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity.Furthermore,mild but sustained Ca2+increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca2+-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways.Based on the Ca2+hypothesis of Alzheimer's disease and recent advances,this Ca2+-activated"silent"degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis.The N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity.Ischemic stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca2+-mediated mechanism,although with much different time courses.It is thus proposed that early interventions to control Ca2+homeostasis at the precl in ical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia.This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.