Dysfunction of NMDA receptors in Alzheimer’s disease

Zhang, Yan; Li, Peiyao; Feng, Jianbo; Wu, Minghua

doi:10.1007/s10072-016-2546-5

Cited by 283Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Dysfunction of NMDA receptors in Alzheimer’s disease

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Zhang, Yan, Li, Peiyao, Feng, Jianbo, Wu, Minghua·2016·Neurological Sciences

DOI 10.1007/s10072-016-2546-5PMC PMC4917574

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Abstract

N-methyl-D-aspartate receptors (NMDARs) play a pivotal role in the synaptic transmission and synaptic plasticity thought to underlie learning and memory. NMDARs activation has been recently implicated in Alzheimer's disease (AD) related to synaptic dysfunction. Synaptic NMDARs are neuroprotective, whereas overactivation of NMDARs located outside of the synapse cause loss of mitochondrial membrane potential and cell death. NMDARs dysfunction in the glutamatergic tripartite synapse, comprising presynaptic and postsynaptic neurons and glial cells, is directly involved in AD. This review discusses that both beta-amyloid (Aβ) and tau perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of NMDARs as a possible convergence point for Aβ and tau toxicity and possible reversible stages of the AD through preventive and/or disease-modifying therapeutic strategies.

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Partial blockade of NMDAR overstimulation with NMDAR antagonists rescues Aβ-induced LTP impairment and cognitive function in various animal models.
“The relevance of NMDAR in AD lends support from studies showing that partial blockade of NMDAR overstimulation with NMDAR antagonists rescues Aβ-induced LTP impairment and cognitive function in various animal models [69].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [69]

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1 retracted

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“Synaptic NMDAR activity suppresses FOXO activity by promoting the Akt-mediated phosphorylation whereas extrasynaptic NMDAR activity stimulates FOXO nuclear import and leads to excitotoxic cell death [41].”
Background
Okadaic acid-induced Tau phosphorylation in rat brain: Role of NMDA receptor
Kamat, P., Rai, S., Swarnkar, S., Shukla, R., Ali, S., Najmi, A. K., & Nath, C. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.01.075 · Cited by 88 · cited 1× · see citing works
“, leading to mitochondrial functional impairments characterized by activation of the permeability transition pores in the inner mitochondrial membrane, cytochrome c release and depletion of ATP, and simultaneous formation of ROS [3].”
Background
Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration
Du, H., Guo, L., Wu, X., Sosunov, A. A., McKhann, G. M., Chen, J. X., & Yan, S. S. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.03.004 · Cited by 86 · cited 1× · see citing works
“A b decreases the phosphorylation of CREB through inactivation of PKA and thus inhibits LTP generation [37].”
Background
Low-frequency (1Hz) repetitive transcranial magnetic stimulation (rTMS) reverses Aβ1–42-mediated memory deficits in rats
Tan, T., Xie, J., Liu, T., Chen, X., Zheng, X., Tong, Z., & Tian, X. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2013.05.001 · Cited by 84 · cited 1× · see citing works
“Low-frequency rTMS reverse the decreased NMDAR levels and deﬁcits in LTP and spatial memory in A b induced AD mouse models [68]. rTMS treatment also improve the cognitive ability and language performance in AD patients suggesting that rTMS may be a effective therapeutic technique in the treatment…”
Amyloid β-Mediated Cell Death of Cultured Hippocampal Neurons Reveals Extensive Tau Fragmentation without Increased Full-length Tau Phosphorylation
Reifert, J. R., Hartung-Cranston, D., & Feinstein, S. C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.234674 · Cited by 80 · cited 1× · see citing works
“Although the investigation into the role of tau in glutamate excitotoxicity is a relatively nascent ﬁeld, tau play a role in mediating A b -induced neuronal death and can induce synaptic dysfunction independently [62].”
Background
A review of the effects of memantine on clinical progression in Alzheimer's disease
Wilkinson, D. (2011) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2788 · Cited by 69 · cited 1× · see citing works
“In clinical trials, memantine has shown signiﬁcant beneﬁts in aspects of cognition such as language, memory, praxis, functional communication and in activities of daily living for AD patients [64].”
Background
Both NR2A and NR2B subunits of the NMDA receptor are critical for long-term potentiation and long-term depression in the lateral amygdala of horizontal slices of adult micePreprint
Müller, T., Albrecht, D., & Gebhardt, C. (2009) · Learning & Memory · doi:10.1101/lm.1398709 · Cited by 65 · cited 1× · see citing works
“Both NR2A and NR2B subunits are critical for the induction of LTP and LTD [9].”
Background
Distribution of N-methyl-d-aspartate receptors (NMDARs) in the developing rat brain
Takai, H., Katayama, K., Uetsuka, K., Nakayama, H., & Doi, K. (2003) · Experimental and Molecular Pathology · doi:10.1016/s0014-4800(03)00030-3 · Cited by 61 · cited 1× · see citing works
“NR2B subunit is mildly expressed in the hippocampus and the temporal region of the cerebral cortex in fetal brain, becomes hardly expressed in adults [6].”
Background
Potential involvement of GRIN2B encoding the NMDA receptor subunit NR2B in the spectrum of Alzheimer’s disease
Andreoli, V., Marco, E. V. D., Trecroci, F., Cittadella, R., Palma, G. D., & Gambardella, A. (2013) · Journal of Neural Transmission · doi:10.1007/s00702-013-1125-7 · Cited by 54 · cited 1× · see citing works
“Statistical indicate that multiple coding variants on the risk haplotype containing rs1806201 may play a role in mediating susceptibility to AD [10].”
Background
A Population-Specific Uncommon Variant in GRIN3A Associated with Schizophrenia
Takata, A., Iwayama, Y., Fukuo, Y., Ikeda, M., Okochi, T., Maekawa, M., Toyota, T., Yamada, K., Hattori, E., Ohnishi, T., et al. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.10.024 · Cited by 51 · cited 1× · see citing works
“And the GRIN3A R480G variant showed strong association with schizophrenia [13].”
Background
Cognitive effects of repetitive transcranial magnetic stimulation in patients with neurodegenerative diseases — Clinician's perspective
Anderková, Ľ., & Rektorová, I. (2014) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2014.01.037 · Cited by 50 · cited 1× · see citing works
“…NMDAR levels and deﬁcits in LTP and spatial memory in A b induced AD mouse models [68]. rTMS treatment also improve the cognitive ability and language performance in AD patients suggesting that rTMS may be a effective therapeutic technique in the treatment of neurodegenerative diseases [69].”
Method
NMDA Reduces Tau Phosphorylation in Rat Hippocampal Slices by Targeting NR2A Receptors, GSK3 β , and PKC Activities
Montigny, A. D., Elhiri, I., Allyson, J., Cyr, M., & Massicotte, G. (2013) · Neural Plasticity · doi:10.1155/2013/261593 · Cited by 39 · cited 1× · see citing works
“GluN2A-contained NMDA receptor induces reduction of tau phosphorylation by a PKC/GSK3 pathway [61].”
Background
Calcium influx through N-methyl-d-aspartate receptors triggers GABA release at interneuron–Purkinje cell synapse in rat cerebellum
Glitsch, M. D. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.10.024 · Cited by 34 · cited 1× · see citing works
“In interneuron–Purkinje cell synapse, the NMDA induce an increase in miniature inhibitory postsynaptic currents (mIPSCs) frequency suggesting the presynaptic NMDARs present on inhibitory axon terminals [24].”
Background
Presynaptic NMDA receptors: Are they dendritic receptors in disguise?
Duguid, I. (2012) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2012.12.004 · Cited by 29 · cited 1× · see citing works
“NMDARs are also located presynaptically where they mediate synaptic transmission and activity-dependent synaptic plasticity in developing neural circuits [23].”
Background
Genetic Variation in N-Methyl-D-Aspartate Receptor Subunit NR3A but Not NR3B Influences Susceptibility to Alzheimer’s Disease
Liu, H.-P., Lin, W.-Y., Liu, S.-H., Wang, W.-F., Tsai, C.-H., Wu, B.-T., Wang, C.-K., & Tsai, F.-J. (2009) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000254757 · Cited by 29 · cited 1× · see citing works
“And also the frequency of Ht2-AG haplotype in GRIN3A gene is higher in AD patients indicates that GRIN3A variant may represent a risk in the development of AD [11].”
Background
A Naturally Occurring Null Variant of the NMDA Type Glutamate Receptor NR3B Subunit Is a Risk Factor of Schizophrenia
Matsuno, H., Ohi, K., Hashimoto, R., Yamamori, H., Yasuda, Y., Fujimoto, M., Umeda‐Yano, S., Saneyoshi, T., Takeda, M., & Hayashi, Y. (2015) · PLoS ONE · doi:10.1371/journal.pone.0116319 · Cited by 23 · cited 1× · see citing works
“People carrying insCGTT which is a genetic variation of the NMDAR NR3B subunit that inserts four bases within the coding region have a predisposition to schizotypal personality traits [12].”
Background
Neramexane: a moderate-affinity NMDA receptor channel blocker: new prospects and indications
Rammes, G. (2009) · Expert Review of Clinical Pharmacology · doi:10.1586/ecp.09.7 · Cited by 22 · cited 1× · see citing works
“Neramexane, a non-competitive NMDAR antagonist, has shown to be efﬁcient in enhancing long-term memory in adult rats as memantine, suggesting that this antagonist may have a potential therapeutic applications [ 65].”
Background
Correction to Supporting Information for Talantova et al., Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss
(2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1511282112 · Cited by 2 · see citing works

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Sorted by citations

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
“The relevance of NMDAR in AD lends support from studies showing that partial blockade of NMDAR overstimulation with NMDAR antagonists rescues Aβinduced LTP impairment and cognitive function in various animal models [69].”
Background
Alzheimer’s disease: Recent treatment strategies
Vaz, M., & Silvestre, S. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173554 · Cited by 547 · see citing works
Effects of air pollution on the nervous system and its possible role in neurodevelopmental and neurodegenerative disorders
Costa, L. G., Cole, T. B., Dao, K., Chang, Y. C., Coburn, J. L., & Garrick, J. M. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107523 · Cited by 490 · see citing works
Calcium signaling and molecular mechanisms underlying neurodegenerative diseases
Pchitskaya, E. I., Александровна, П. Е., & Борисович, Б. И. (2017) · Cell Calcium · doi:10.1016/j.ceca.2017.06.008 · Cited by 346 · see citing works
“In case of hippocampus, TRPC6 and Orai2 were recently identified as SOCE-forming channels in hippocampal neurons (Zhang et al., 2016a).”
BackgroundInfluential
Comprehensive review of mechanisms of pathogenesis involved in Alzheimer’s disease and potential therapeutic strategies
Sharma, P., Srivastava, P., Seth, A., Tripathi, P. N., Banerjee, A. G., & Shrivastava, S. K. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.12.006 · Cited by 331 · see citing works
Phytochemicals as inhibitors of NF-κB for treatment of Alzheimer’s disease
Seo, E.-J., Fischer, N., & Efferth, T. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2017.11.030 · Cited by 265 · see citing works
“The loss of mitochondrial membrane potential causing cell death, which is directly involved in AD pathogenesis, is attenuated [86].”
Background
Depression in neurodegenerative diseases: Common mechanisms and current treatment options
Galts, C., Bettio, L. E. B., Jewett, D. C., Yang, C. C., Brocardo, P. S., Rodrigues, A. L. S., Thacker, J. S., & Gil‐Mohapel, J. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.04.002 · Cited by 268 · see citing works
Alzheimer's disease: a comprehensive review of epidemiology, risk factors, symptoms diagnosis, management, caregiving, advanced treatments and associated challenges
Safiri, S., Jolfayi, A. G., Fazlollahi, A., Morsali, S., Sarkesh, A., Sorkhabi, A. D., Golabi, B., Aletaha, R., Asghari, K. M., Hamidi, S., et al. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1474043 · Cited by 242 · see citing works
“NMDA receptor dysfunction, involving pre-and postsynaptic neurons and glial cells, directly aﬀects AD (375).”
Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors
Temido‐Ferreira, M., Ferreira, D. G., Batalha, V. L., Marques-Morgado, I., Coelho, J. E., Pereira, P., Gomes, R., Pinto, A., Carvalho, S., Canas, P. M., et al. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0110-9 · Cited by 181 · see citing works
Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease
Yu, S. P., Jiang, M. Q., Shim, S. S., Pourkhodadad, S., & Wei, L. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00636-1 · Cited by 165 · see citing works
The basis of cellular and regional vulnerability in Alzheimer’s disease
Mrdjen, D., Fox, E. J., Bukhari, S. A., Montine, K. S., Bendall, S. C., & Montine, T. J. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02054-4 · Cited by 155 · see citing works
NMDA and AMPA receptors dysregulation in Alzheimer's disease
Babaei, P. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174310 · Cited by 149 · see citing works
Involvement of extrasynaptic glutamate in physiological and pathophysiological changes of neuronal excitability
Pál, B. Z. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2837-5 · Cited by 135 · see citing works
Amyloid Beta-Related Alterations to Glutamate Signaling Dynamics During Alzheimer’s Disease Progression
Findley, C. A., Bartke, A., Hascup, K. N., & Hascup, E. R. (2019) · ASN NEURO · doi:10.1177/1759091419855541 · Cited by 124 · see citing works
“(Hardingham et al., 2002; Hardingham and Bading, 2003; Bezprozvanny and Mattson, 2008; Zhang et al., 2016).”
Influential
NMDA Receptor Antagonists: Repositioning of Memantine as a Multitargeting Agent for Alzheimer's Therapy
Kabir, M. T., Sufian, M. A., Uddin, M. S., Begum, M. M., Akhter, S., Islam, A., Mathew, B., Islam, M. S., Amran, M. S., & Ashraf, G. M. (2019) · Current Pharmaceutical Design · doi:10.2174/1381612825666191011102444 · Cited by 120 · see citing works
Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications
Giri, P. M., Banerjee, A., Ghosal, A., & Layek, B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073995 · Cited by 123 · see citing works
“Overactivation of NMDA receptors has been observed in AD patients, leading to a higher level of glutamate in the brain [28].”
Background
Calcium-Handling Defects and Neurodegenerative DiseasePreprint
Schrank, S., Barrington, N. M., & Stutzmann, G. E. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a035212 · Cited by 114 · see citing works
Dysregulation of Intracellular Calcium Signaling in Alzheimer's Disease
Александровна, П. Е., Pchitskaya, E. I., & Борисович, Б. И. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7506 · Cited by 102 · see citing works
“It was reported that in early disease stages, Ab activates NMDAR and induces rapid Ca elevation in neurons (40, 87, 99, 134).”
Background
Aβ Oligomers Dysregulate Calcium Homeostasis by Mechanosensitive Activation of AMPA and NMDA Receptors
Fani, G., Mannini, B., Vecchi, G., Cascella, R., Cecchi, C., Dobson, C. M., Vendruscolo, M., & Chiti, F. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00811 · Cited by 102 · see citing works
Toxoplasma gondii alters NMDAR signaling and induces signs of Alzheimer’s disease in wild-type, C57BL/6 mice
Torres, L., Robinson, S.-A., Kim, D.-G., Yan, A., Cleland, T. A., & Bynoe, M. S. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1086-8 · Cited by 95 · see citing works
“The potent downregulation or loss of NMDAR is strongly indicative of the Aβ-induced synaptic depression and impaired synaptic plasticity that is seen in AD [41, 42].”
Background
Ca 2+ homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles
Wang, X., & Zheng, W. (2019) · The FASEB Journal · doi:10.1096/fj.201801751r · Cited by 97 · see citing works
“Food and Drug Administration– approved extrasynaptic NMDAR antagonist memantine (107, 108), more therapeutic strategies for AD may also be developed by regulating the NMDAR system.”
Background
Mechanisms of neuroplasticity and brain degeneration: strategies for protection during the aging process
Viel, T., Toricelli, M., Pereira, A. R., Souza Abrao, G., Malerba, H., Maia, J., & Buck, H. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.286952 · Cited by 102 · see citing works
“…high densities of β-amyloid plaques in the hippocampus are known to induce increased replacement of NMDA Glu-N2A subunits with Glu-N2B (via calpains) facilitating receptor binding to SAP-102, which presents high mobility for extra-synaptic regions (Parsons and Raymond, 2014; Zhang et al., 2016).”
Building a Bridge Between NMDAR-Mediated Excitotoxicity and Mitochondrial Dysfunction in Chronic and Acute Diseases
Mira, R. G., & Cerpa, W. F. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00924-0 · Cited by 96 · see citing works
Reappraisal of metabolic dysfunction in neurodegeneration: Focus on mitochondrial function and calcium signaling
Jadiya, P., Garbincius, J. F., & Elrod, J. W. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01224-4 · Cited by 94 · see citing works
Obesity as a Risk Factor for Alzheimer’s Disease: Implication of Leptin and Glutamate
Lloret, A., Monllor, P., Esteve, D., Cervera‐Ferri, A., & Lloret, M.-Á. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00508 · Cited by 90 · see citing works
“Interestingly, in AD the aforementioned overactivation is produced in extrasynaptic NMDA receptors rather than in synaptic NMDA receptors (Zhang et al., 2016).”
Background
Current Pharmacotherapy and Multi-Target Approaches for Alzheimer’s Disease
Cheong, S. L., Tiew, J. K., Fong, Y. H., Leong, H. W., Chan, Y. M., Chan, Z. L., & Kong, E. W. J. (2022) · Pharmaceuticals · doi:10.3390/ph15121560 · Cited by 89 · see citing works
“Thus, free ROS production is favored, subsequently causing an increase in oxidative stress and altered synapse function [24].”
Background
Drug development for Alzheimer’s disease: Review
Lao, K., Ji, N., Zhang, X., Qiao, W., Tang, Z., & Gou, X. (2019) · Journal of drug targeting · doi:10.1080/1061186x.2018.1474361 · Cited by 86 · see citing works
“The NMDARs are cationic channels gated by the neurotransmitter glutamate which play an essential role in excitatory transmission, synaptic integration, learning and memory [13].”
Background
GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways
Demuro, S., Martino, R. M. C. D., Ortega, J. A., & Cavalli, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22169098 · Cited by 85 · see citing works
“nMDARs are the primary channel that mediates Ca2+ signals in hippocampal neurons and contribute to the expression of long-term potentiation (LTP) and long-term depression (LTD), which are two major forms of long-lasting synaptic plasticity, by employing both NR2A and NR2B subunits [88].”
Background
Naturally Occurring Antioxidant Therapy in Alzheimer’s Disease
Collins, A. E., Saleh, T. M., & Kalisch, B. E. (2022) · Antioxidants · doi:10.3390/antiox11020213 · Cited by 87 · see citing works
Could Alzheimer’s Disease Originate in the Periphery and If So How So?
Morris, G., Berk, M., Maes, M. H. J., & Puri, B. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1092-y · Cited by 83 · see citing works
“tate (NMDA) receptors, which has been repeatedly reported in AD patients [254], via oxidation of cysteine groups on key”
Background
An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer’s Disease
Ratan, Y., Rajput, A., Maleysm, S., Pareek, A., Jain, V. K., Pareek, A., Kaur, R., & Singh, G. (2023) · Biomedicines · doi:10.3390/biomedicines11051398 · Cited by 87 · see citing works
“These ﬁndings demonstrate that the partial inhibition of NMDAR jaded stimulation with antagonists of NMDAR restores A β -initiated long-term potentiation (LTP) deﬁcits and cognitive performance in distinct animal models, suggesting the importance of NMDAR in AD [99].”
Background
Calcium signalling: A common target in neurological disorders and neurogenesis
Glaser, T., Arnaud-Sampaio, V. F., Lameu, C., & Ulrich, H. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.12.002 · Cited by 75 · see citing works
Molecular mechanisms of neurodegeneration in the entorhinal cortex that underlie its selective vulnerability during the pathogenesis of Alzheimer's disease
Olajide, O. J., Suvanto, M. E., & Chapman, C. A. (2021) · Biology Open · doi:10.1242/bio.056796 · Cited by 71 · see citing works
A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy
Gadhave, K., Kumar, D., Uversky, V. N., & Giri, R. (2020) · Medicinal Research Reviews · doi:10.1002/med.21719 · Cited by 70 · see citing works
“Here, synaptic NMDA receptors promote calcium entry leading to the induction of the CREB phosphorylation, whereas extrasynaptic NMDA receptors show the opposite effects and initiate the CREB shut‐off pathway.364 Transcriptional activity of CREB and associated LTP generation are decreased in AD mostly due to the Aβ‐ind…”
BackgroundInfluential
Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors
Jakaria, M., Park, S., Haque, M. E., Karthivashan, G., Kim, I., Ganesan, P., & Choi, D. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00307 · Cited by 70 · see citing works
A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice
Companys‐Alemany, J., Turcu, A. L., Bellver‐Sanchís, A., Loza, M. I., Brea, J. M., Canudas, A. M., Leiva, R., Vázquez, S., Pallàs, M., & Griñán‐Ferré, C. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12030284 · Cited by 64 · see citing works
“On the other hand, there is accumulating evidence that several neurotransmitter pathways, such as acetylcholine, dopamine, glutamate, and serotonin [12] are involved in the pathological alterations of AD [13,14].”
Background
Agathisflavone, a flavonoid derived from Poincianella pyramidalis (Tul.), enhances neuronal population and protects against glutamate excitotoxicity
Souza, C. D. S., Grangeiro, M. S., Pereira, É. P. L., dos Santos, C. C., da Silva, A. B., Sampaio, G. P., Figueiredo, D. D. R., David, J. M., David, J. P., da Silva, V. D. A., et al. (2018) · NeuroToxicology · doi:10.1016/j.neuro.2018.02.001 · Cited by 62 · see citing works
The Role of D-Amino Acids in Alzheimer’s Disease
Piubelli, L., Murtas, G., Rabattoni, V., & Pollegioni, L. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201217 · Cited by 62 · see citing works
“As stated above, dysfunctional glutamatergic transmission mediated by altered NMDA receptor activity has been proposed to contribute to the pathogenesis of AD [41, 76, 117].”
Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease
Marotta, G., Basagni, F., Rosini, M., & Minarini, A. (2020) · Molecules · doi:10.3390/molecules25174005 · Cited by 61 · see citing works
Homocysteine and Age-Related Central Nervous System Diseases: Role of Inflammation
Tawfik, A. M., Elsherbiny, N. M., Zaidi, Y., & Rajpurohit, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126259 · Cited by 61 · see citing works
“These changes are concomitant with NMDAR activation and oxidative stress, ultimately resulting in AD pathology [30].”
Background
Role of GPCR signaling and calcium dysregulation in Alzheimer's disease
Sushma, & Mondal, A. C. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.103414 · Cited by 56 · see citing works
Therapeutic Strategies to Target Calcium Dysregulation in Alzheimer’s Disease
Calvo-Rodríguez, M., Kharitonova, E. K., & Bacskai, B. J. (2020) · Cells · doi:10.3390/cells9112513 · Cited by 59 · see citing works
“Aβ42 peptides interact with NMDARs, potentiating their activity and leading to increased Ca2+ influx, thus contributing to the synapse loss observed in AD [44,45].”
Background
Time-dependent effect of oligomeric amyloid-β (1–42)-induced hippocampal neurodegeneration in rat model of Alzheimer’s disease
Chennakesavan, K., Saravanan, N., Essa, M. M., Guillemin, G. J., Jayachandran, S. K., & Anusuyadevi, M. (2018) · Neurological Research · doi:10.1080/01616412.2018.1544745 · Cited by 58 · see citing works
“regulates the NMDARs and disturbs the ionic balance between synaptic and extrasynaptic NMDAR signaling [13,14], but the exact mechanisms underlying Aβ-”
Background
Regulation of Melatonin and Neurotransmission in Alzheimer’s Disease
Roy, J., Tsui, K. C., Ng, J., Fung, M., & Lim, L. W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136841 · Cited by 56 · see citing works
Understanding the Modulatory Effects of Cannabidiol on Alzheimer’s Disease
Xiong, Y., & Lim, C. (2021) · Brain Sciences · doi:10.3390/brainsci11091211 · Cited by 60 · see citing works
“Increased extracellular glutamate excessively activates both synaptic and extrasynaptic N-methyl-D-aspartate (NMDA) receptors, leading to intense transient influx of Ca2+ and activation of signaling pathways responsible for neuronal dysfunction and cell death [6,7].”
Background
Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity
Olajide, O. J., Gbadamosi, I., Yawson, E. O., Arogundade, T. T., Lewu, F. S., Ogunrinola, K. Y., Adigun, O. O., Bamisi, O., Lambe, E., Arietarhire, L. O., et al. (2021) · Journal of Molecular Neuroscience · doi:10.1007/s12031-020-01747-w · Cited by 55 · see citing works
Role of Receptors in Relation to Plaques and Tangles in Alzheimer’s Disease Pathology
Sharma, K., Pradhan, S., Duffy, L. K., Yeasmin, S., Bhattarai, N., & Schulte, M. K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222312987 · Cited by 58 · see citing works
“The synapse receptor proteins modulate the extracellular glutamate levels and are considered deregulated in AD pathology [64].”
Background
Insulin and serine metabolism as sex-specific hallmarks of Alzheimer’s disease in the human hippocampus
Maffioli, E., Murtas, G., Rabattoni, V., Badone, B., Tripodi, F., Iannuzzi, F., Licastro, D., Nonnis, S., Rinaldi, A. M., Motta, Z., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111271 · Cited by 54 · see citing works
NMDA Receptors: Distribution, Role, and Insights into Neuropsychiatric Disorders
Beaurain, M., Salabert, A., Payoux, P., Gras, E., & Talmont, F. (2024) · Pharmaceuticals · doi:10.3390/ph17101265 · Cited by 55 · see citing works
“The pathophysiology of AD encompasses both structural and functional abnormalities, particularly in the hippocampus and neocortex, which are particularly involved in memory and cognition [143].”
Background
In Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons
Najm, R., Zalocusky, K. A., Zilberter, M., Yoon, S. Y., Hao, Y., Koutsodendris, N., Nelson, M., Rao, A., Taubes, A., Jones, E. A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107962 · Cited by 52 · see citing works
Synaptic plasticity modulation by circulating peptides and metaplasticity: Involvement in Alzheimer’s disease
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Authors: Zhang, Y., Li, P., Feng, J., & Wu, M.
Affiliations: Central South University (CN)
Corresponding author: Wu, Minghua
ORCID: Zhang, Yan
Li, Peiyao
Feng, Jianbo
Wu, Minghua
Venue: Neurological Sciences
Publisher: Springer Science and Business Media LLC
Published: 2016-03-12
Volume: 37
Issue: 7
Pages: 1039-1047
ISSN: 1590-1874 (ISSN-L)
1590-3478
DOI: 10.1007/s10072-016-2546-5
PMC: PMC4917574
OpenAlex: W2293608890
Cited by: 282
References: 72
Citations by year: 2026: 15 · 2025: 30 · 2024: 36 · 2023: 29 · 2022: 29 · 2021: 27 · 2020: 39 · 2019: 23 · 2018: 35 · 2017: 15 · 2016: 3
FWCI: 2.97
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (unspecified)
Locations: Neurological Sciences (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: NMDA receptor, Alzheimer's disease, synaptic dysfunction, tripartite synapse, amyloid-beta, tau protein, glutamate release, astrocytes, synaptic plasticity, mitochondrial membrane potential, neuroprotection, disease-modifying therapy
MeSH terms: Alzheimer Disease, Humans, Synapses, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, tau Proteins

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