NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies
NMDA receptors (NMDARs) are widely distributed throughout the central nervous system (CNS) and play pivotal roles in normal physiological processes such as synaptic plasticity, learning, and memory. Substantial evidence indicates that NMDAR dysfunction, particularly excessive calcium influx, critica...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1604378/full |
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| author | Keyi Zhang Keyi Zhang Ming Wen Ming Wen Xinyue Nan Xinyue Nan Shuaizhu Zhao Shuaizhu Zhao Hao Li Hao Li Yanping Ai Yanping Ai Houze Zhu Houze Zhu |
| author_facet | Keyi Zhang Keyi Zhang Ming Wen Ming Wen Xinyue Nan Xinyue Nan Shuaizhu Zhao Shuaizhu Zhao Hao Li Hao Li Yanping Ai Yanping Ai Houze Zhu Houze Zhu |
| author_sort | Keyi Zhang |
| collection | DOAJ |
| description | NMDA receptors (NMDARs) are widely distributed throughout the central nervous system (CNS) and play pivotal roles in normal physiological processes such as synaptic plasticity, learning, and memory. Substantial evidence indicates that NMDAR dysfunction, particularly excessive calcium influx, critically contributes to the pathogenesis of major neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Dysregulated glutamatergic signaling synergizes with pathological protein aggregation (e.g., Aβ, α-synuclein, mutant huntingtin) to drive neuronal loss. We systematically delineate NMDAR-related mechanisms underlying neurodegeneration, highlighting spatial-specific roles (e.g., synaptic NMDAR-mediated neuroprotection versus extrasynaptic NMDAR-mediated excitotoxicity) and crosstalk with mitochondrial dysfunction and oxidative stress. We critically evaluate current therapeutic strategies targeting NMDARs, including subunit-selective modulators, downstream effector modulation, and glutamate transporter modulation designed to restore NMDAR homeostasis. Consequently, NMDARs and their modulators represent promising therapeutic targets for these refractory conditions. This review comprehensively summarizes current research on the involvement of NMDARs and the glutamatergic system in neurodegenerative diseases. Furthermore, we discuss the clinical application of NMDAR-targeting agents and explore emerging therapeutic strategies focused on modulating NMDAR-related pathways. This article aims to provide a reference for elucidating the molecular mechanisms underlying these neurodegenerative disorders and to highlight potential avenues for future drug development. |
| format | Article |
| id | doaj-art-97cc5378b63f4242bfefbd37d87fd6fa |
| institution | Kabale University |
| issn | 1663-4365 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj-art-97cc5378b63f4242bfefbd37d87fd6fa2025-08-20T03:56:00ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652025-07-011710.3389/fnagi.2025.16043781604378NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategiesKeyi Zhang0Keyi Zhang1Ming Wen2Ming Wen3Xinyue Nan4Xinyue Nan5Shuaizhu Zhao6Shuaizhu Zhao7Hao Li8Hao Li9Yanping Ai10Yanping Ai11Houze Zhu12Houze Zhu13Innovation Center for Brain Medical Sciences, The Ministry of Education of the People’s Republic of China, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInnovation Center for Brain Medical Sciences, The Ministry of Education of the People’s Republic of China, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurosurgery, Wuhan Hankou Hospital, Hankou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, ChinaInnovation Center for Brain Medical Sciences, The Ministry of Education of the People’s Republic of China, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInnovation Center for Brain Medical Sciences, The Ministry of Education of the People’s Republic of China, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInnovation Center for Brain Medical Sciences, The Ministry of Education of the People’s Republic of China, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInnovation Center for Brain Medical Sciences, The Ministry of Education of the People’s Republic of China, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurology, Wuhan Hankou Hospital, Wuhan, ChinaInnovation Center for Brain Medical Sciences, The Ministry of Education of the People’s Republic of China, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Physiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, ChinaNMDA receptors (NMDARs) are widely distributed throughout the central nervous system (CNS) and play pivotal roles in normal physiological processes such as synaptic plasticity, learning, and memory. Substantial evidence indicates that NMDAR dysfunction, particularly excessive calcium influx, critically contributes to the pathogenesis of major neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Dysregulated glutamatergic signaling synergizes with pathological protein aggregation (e.g., Aβ, α-synuclein, mutant huntingtin) to drive neuronal loss. We systematically delineate NMDAR-related mechanisms underlying neurodegeneration, highlighting spatial-specific roles (e.g., synaptic NMDAR-mediated neuroprotection versus extrasynaptic NMDAR-mediated excitotoxicity) and crosstalk with mitochondrial dysfunction and oxidative stress. We critically evaluate current therapeutic strategies targeting NMDARs, including subunit-selective modulators, downstream effector modulation, and glutamate transporter modulation designed to restore NMDAR homeostasis. Consequently, NMDARs and their modulators represent promising therapeutic targets for these refractory conditions. This review comprehensively summarizes current research on the involvement of NMDARs and the glutamatergic system in neurodegenerative diseases. Furthermore, we discuss the clinical application of NMDAR-targeting agents and explore emerging therapeutic strategies focused on modulating NMDAR-related pathways. This article aims to provide a reference for elucidating the molecular mechanisms underlying these neurodegenerative disorders and to highlight potential avenues for future drug development.https://www.frontiersin.org/articles/10.3389/fnagi.2025.1604378/fullNMDA receptors (N-methyl-D-aspartate receptors)neurodegenerative diseaseexcitotoxicityglutamateAlzheimer’s disease (AD)Huntington’s disease (HD) |
| spellingShingle | Keyi Zhang Keyi Zhang Ming Wen Ming Wen Xinyue Nan Xinyue Nan Shuaizhu Zhao Shuaizhu Zhao Hao Li Hao Li Yanping Ai Yanping Ai Houze Zhu Houze Zhu NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies Frontiers in Aging Neuroscience NMDA receptors (N-methyl-D-aspartate receptors) neurodegenerative disease excitotoxicity glutamate Alzheimer’s disease (AD) Huntington’s disease (HD) |
| title | NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies |
| title_full | NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies |
| title_fullStr | NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies |
| title_full_unstemmed | NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies |
| title_short | NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies |
| title_sort | nmda receptors in neurodegenerative diseases mechanisms and emerging therapeutic strategies |
| topic | NMDA receptors (N-methyl-D-aspartate receptors) neurodegenerative disease excitotoxicity glutamate Alzheimer’s disease (AD) Huntington’s disease (HD) |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1604378/full |
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