Dysregulation of synaptic and extrasynaptic N-methyl-D-aspartate receptors induced by amyloid-β

• Published in: Neuroscience bulletin Vol. 29; no. 6; pp. 752 - 760
• Main Authors: Wang, Zhi-Cong, Zhao, Jie, Li, Shao
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2013
• Subjects: Alzheimer Disease - metabolism; Amyloid beta-Peptides - metabolism; Anatomy; Anesthesiology; Animals; Biomedical and Life Sciences; Biomedicine; Human Physiology; Humans; N-甲基-D-天冬氨酸受体; Neurology; Neurosciences; NMDA受体; Pain Medicine; Receptors, N-Methyl-D-Aspartate - metabolism; Review; Synapses - metabolism; 功能失调; 淀粉样蛋白; 神经保护作用; 神经毒性; 突触; 老年痴呆症; synaptic NMDA receptor; amyloid-β; neurotoxicity; extrasynaptic NMDA receptor
• ISSN: 1673-7067; 1995-8218
• DOI: 10.1007/s12264-013-1383-2

The toxicity of amyloid-beta（Aβ） is strongly associated with Alzheimer’s disease（AD）,which has a high incidence in the elderly worldwide.Recent evidence showed that alteration in the activity of N-methyl-D-aspartate receptors（NMDARs） plays a key role in Aβ-induced neurotoxicity.However,the activation of synaptic and extrasynaptic NMDARs has distinct consequences for plasticity,gene regulation,neuronal death,and Aβ production.This review focuses on the dysregulation of synaptic and extrasynaptic NMDARs induced by Aβ.On one hand,Aβ downregulates the synaptic NMDAR response by promoting NMDAR endocytosis,leading to either neurotoxicity or neuroprotection.On the other hand,Aβ enhances the activation of extrasynaptic NMDARs by decreasing neuronal glutamate uptake and inducing glutamate spillover,subsequently causing neurotoxicity.In addition,selective enhancement of synaptic activity by low doses of NMDA,or reduction of extrasynaptic activity by memantine,a non-competitive NMDAR antagonist,halts Aβ-induced neurotoxicity.Therefore,future neuroprotective drugs for AD should aim at both the enhancement of synaptic activity and the disruption of extrasynaptic NMDAR-dependent death signaling.