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Dysfunction of NMDA receptors in Alzheimer’s disease
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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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![Fig. 1 Structure and domain organization of NMDA receptors. Linear representation of the subunit polypeptide chain and schematic illustration of the subunit topology. NMDARs subunits have a modular structure composed of two extracellular domains [the ATD (green) and the LBD (yellow)]; a TMD (cyan) that forms part of the ion channel pore; and an intracellular CTD. The LBD is defined by two segments of amino acids termed S1 and S2. The TMD contains three membrane-spanning helices (M1, M3, and M4) and a membrane re-entrant loop (M2)](/paper-figures/5a9f61267ae6405486f516579de77eb5/dysfunction-of-nmda-receptors-in-alzheimers-disease-figure-1.jpg)
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“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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Phytochemicals as inhibitors of NF-κB for treatment of Alzheimer’s disease
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“It was reported that in early disease stages, Ab activates NMDAR and induces rapid Ca elevation in neurons (40, 87, 99, 134).”
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“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.”
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“…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).”
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“Interestingly, in AD the aforementioned overactivation is produced in extrasynaptic NMDA receptors rather than in synaptic NMDA receptors (Zhang et al., 2016).”
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“Thus, free ROS production is favored, subsequently causing an increase in oxidative stress and altered synapse function [24].”
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“The NMDARs are cationic channels gated by the neurotransmitter glutamate which play an essential role in excitatory transmission, synaptic integration, learning and memory [13].”
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Demuro, S., Martino, R. M. C. D., Ortega, J. A., & Cavalli, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22169098 · Cited by 88
“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].”
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“tate (NMDA) receptors, which has been repeatedly reported in AD patients [254], via oxidation of cysteine groups on key”
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nNOS – CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages
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“Extrasynaptic NMDARs promote inactivation of ERK, dephosphorylation of CREB, and phosphorylation of p38, while synaptic NMDARs provide a neuroprotective effect by inducing the expression of survival genes and inhibiting the expression of apoptotic genes (Zhang et al., 2016).”
BackgroundSelf-citationBashir, S., Uzair, M., Abualait, T., Arshad, M. M. U. D., Khallaf, R. A., Niaz, A., Thani, Z., Yoo, W., Túnez, I., Demirtaş-Tatlıdede, A., et al. (2022) · Molecular Medicine Reports · doi:10.3892/mmr.2022.12625 · Cited by 42
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“Furthermore, Aβ regulates the NMDA receptors (NMDARs) and disrupts the ionic balance between synaptic and extra synaptic NMDAR signaling [72,73]; however, the precise mechanism behind Aβ-mediated excitotoxicity stills remains obscure.”
BackgroundJurcău, A., & Simion, A. (2020) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527319666200303121016 · Cited by 38
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“Nevertheless, the overactivation of NMDARs is a crucial factor that promotes the increase of intracellular Ca2+ levels leading to synaptic dysfunction and neuronal loss [2].”
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Neurobiological mechanisms in the kynurenine pathway and major depressive disorder
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Stem Cell Therapy: A Prospective Treatment for Alzheimer's Disease
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MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats
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“Indeed, Aβ accumulation has membrane prooxidative effects due to an increased production of hydrogen peroxide and hydroxyl radicals (Butterfield et al., 2010; Mota et al., 2014; Zhang et al., 2016).”
InfluentialThe neurotransmitter puzzle of Alzheimer's: Dissecting mechanisms and exploring therapeutic horizons
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Reversal of Calcium Dysregulation as Potential Approach for Treating Alzheimer's Disease
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“is closely related to a variety of neurodegenerative diseases [46, 47], in which the balance of amino acids and”
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“Such multiple target drugs developed for AD have targeted two or more of known targets (cholinesterases, BACE1, MAO, NMDA) or have disease progression retarding properties, such as metal chelation, reduce oxidative stress or have anti-inflammatory potential, or can prevent Aβ or tau aggregation [14].”
BackgroundRafe, M. R., Saha, P., & Bello, S. T. (2024) · Behavioural Brain Research · doi:10.1016/j.bbr.2024.115173 · Cited by 29
Exploring the Role of P2X Receptors in Alzheimer’s Disease
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PCDH7 interacts with GluN1 and regulates dendritic spine morphology and synaptic function
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“Specifically, Abeta oligomers affect Ca 2+ entry through NMDARs (Snyder et al. , 2005; Zhang et al. , 2016) and/or voltage-gated calcium channels (VGCCs) (Nimmrich et al. , 2008; Thibault et al. , 2012; Wang & Mattson, 2013).”
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“(Bading, 2017; Zhang et al., 2016) Increased intracellular Ca2+ also directly promotes genomic death responses through cytosol to nucleus translocation of Forkhead transcription factor FoxO3a (Dick and Bading, 2010) and promotes beta-secretase activity and cleavage of amyloid precursor protein (APP) into Aβ, creating…”
BackgroundXie, J., Wu, S., Szadowski, H., Min, S., Yang, Y., Bowman, A. B., Rochet, J., Freeman, J. L., & Yuan, C. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105023 · Cited by 27
“Neurons with developmental Pb exposure have increased NMDAR, CaMKII, and intracellular Ca concentrations.”
InfluentialHamidi, N., Nozad, A., Milan, H. S., & Amani, M. (2019) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2019.01.007 · Cited by 28
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“Over-activation of NMDARs is proven to cause injury to neurons, which can lead to both acute and long-term disorders of the nervous system, such as Alzheimer ’ s dementia (Liu et al., 2019; Zhang et al., 2016).”
Glutamate Metabolism in Mitochondria is Closely Related to Alzheimer’s Disease
Song, J., Yang, X., Zhang, M., Wang, C., & Chen, L. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210595 · Cited by 25
“AsanNMDAreceptor antagonist,memantineisbelievedtoreducetheexci-tatoryneurotoxicityofglutamate[210–212]andhas shownmoderateefficacyandsafetyinthetreatment ofmoderatetosevereAD[213].”
Klotho protein: Its role in aging and central nervous system pathology
Бокша, И. С., Prokhorova, T. A., Savushkina, O. K., & Терешкина, Е. Б. (2017) · Biochemistry (Moscow) · doi:10.1134/s0006297917090024 · Cited by 27
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“Another type of treatment - N-methyl-D-aspartic acid (NMDA) receptor agonists - target overly active glutamate receptors and prevent neural degeneration by decreasing the buildup of phosphorylated tau (Zhang et al. 2016).”
BackgroundAnimal Models of Alzheimer’s Disease
Newman, M., Kretzschmar, D., Khan, I., Chen, M., Verdile, G., & Lardelli, M. T. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809468-6.00040-1 · Cited by 25
Metadata
- Authors
- Zhang, Y., Li, P., Feng, J., & Wu, M.
- Affiliations
- Central South University (CN)
- Corresponding author
- Wu, Minghua
- Venue
- Neurological Sciences
- Published
- 2016-03-12
- Volume
- 37
- Issue
- 7
- Pages
- 1039-1047
- ISSN
- 1590-1874 (ISSN-L)
- 1590-3478
- 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
- Locations
- Neurological Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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