title: Modulating the Balance of Synaptic and Extrasynaptic NMDA Receptors Shows Positive Effects against Amyloid-β-Induced Neurotoxicity.
abstract: Alzheimer's disease (AD) patients suffer a disturbance in the balance between synaptic (GluN2A, mediating the protective pathway) and extrasynaptic NMDA receptors (NMDARs) (GluN2B, mediating the excitotoxic pathway), and, therefore, restoring the balance of GluN2A and GluN2B should be beneficial for AD. In this study, the GluN2B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effect on amyloid-β (Aβ)-induced long-term potentiation deficits. Enhancing the activity of GluN2A had a protective effect against Aβ, and specific activation of GluN2A and inhibition of GluN2B showed a better protective effect. In Aβ ICV-injected animals, the combination of ifenprodil and D-cycloserine (a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests (nest building, novel object recognition, and Morris water maze) than ifenprodil (Morris water maze) or D-cycloserine (nest building) alone. Signal pathway analysis showed that Aβ disturbed the GluN2A/GluN2B-related pathway. The ratio of GluN2A to GluN2B decreased in Aβ-treated animals, and TORC dephosphorylation and ERK1/2 activation, which could be initiated by GluN2A, also decreased in the hippocampal tissues of Aβ-treated animals. As a result, the activation of CREB and the content of brain-derived BDNF decreased. The combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone, indicating that Aβ-induced toxicology was mediated both by functionally inhibiting GluN2A and enhancing GluN2B. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Aβ-induced neurotoxicity, suggesting that modulation of the balance between GluN2A and GluN2B could be a potential strategy for AD drug development and therapy.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.|Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangdong Sheng, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Cheng
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
authors.forename: Wen-Xia
authors.initials: WX
authors.lastname: Zhou
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Zhang
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D003523:Cycloserine / Q000627:therapeutic use; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009425:Nesting Behavior / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000473:pathology*; D010446:Peptide Fragments / Q000633:toxicity; D010880:Piperidines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D000963:Antimetabolites; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); D016202:N-Methylaspartate; D003523:Cycloserine; C010739:ifenprodil
keywords: Alzheimer’s disease; GluN2A; GluN2B; amyloid-β; balance