Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine
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Oxidative stress is a major aspect of Alzheimer disease (AD) pathology. We have investigated the relationship between oxidative stress and neuronal binding of Abeta oligomers (also known as ADDLs). ADDLs are known to accumulate in brain tissue of AD patients and are considered centrally related to pathogenesis. Using hippocampal neuronal cultures, we found that ADDLs stimulated excessive formation of reactive oxygen species (ROS) through a mechanism requiring N-methyl-d-aspartate receptor (NMDA-R) activation. ADDL binding to neurons was reduced and ROS formation was completely blocked by an antibody to the extracellular domain of the NR1 subunit of NMDA-Rs. In harmony with a steric inhibition of ADDL binding by NR1 antibodies, ADDLs that were bound to detergent-extracted synaptosomal membranes co-immunoprecipitated with NMDA-R subunits. The NR1 antibody did not affect ROS formation induced by NMDA, showing that NMDA-Rs themselves remained functional. Memantine, an open channel NMDA-R antagonist prescribed as a memory-preserving drug for AD patients, completely protected against ADDL-induced ROS formation, as did other NMDA-R antagonists. Memantine and the anti-NR1 antibody also attenuated a rapid ADDL-induced increase in intraneuronal calcium, which was essential for stimulated ROS formation. These results show that ADDLs bind to or in close proximity to NMDA-Rs, triggering neuronal damage through NMDA-R-dependent calcium flux. This response provides a pathologically specific mechanism for the therapeutic action of memantine, indicates a role for ROS dysregulation in ADDL-induced cognitive impairment, and supports the unifying hypothesis that ADDLs play a central role in AD pathogenesis.
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oAβ may directly interact with NMDAR, as NMDAR subunits can co-immunoprecipitate with oAβ.
“oAβ may directly interact with NMDAR, as NMDAR subunits can co-immunoprecipitate with oAβ [63].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [63]
Aβ oligomers can target and activate NMDAR, leading to a rapid increase in neuronal calcium levels and reactive oxygen species production in mature hippocampal neurons in culture.
“Aβ oligomers can target and activate NMDAR leading to a rapid increase in neuronal calcium levels and ROS production in mature hippocampal neurons in culture [75].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [75]
Memantine blocks excessive calcium entry through the NMDAR channel and Aβ-induced oxidative stress, providing a specific biological mechanism for its therapeutic action.
“During pathological activation of the NMDAR, memantine blocks excessive calcium entry through the channel and Aβ-induced OS, providing a specific biological mechanism for the therapeutic action of memantine.”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [75]
NMDAR knock-down abrogates neuronal oxidative stress induced by Aβ oligomers, which is mediated by aberrant activation of NMDARs.
“NMDAR knock-down also abrogates neuronal oxidative stress induced by Aβ oligomers, which is mediated by aberrant activation of NMDARs (De Felice et al., 2007).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as De Felice et al., 2007
NMDARs co-immunoprecipitate with Aβ oligomers from detergent-extracted oligomer-treated rat synaptosomal membranes, and an N-terminal anti-NR1 antibody markedly reduced oligomer binding to dendrites.
“NMDARs co-immunoprecipitate with Aβ oligomers from detergent-extracted oligomer-treated rat synaptosomal membranes, and an N-terminal anti-NR1 antibody markedly reduced oligomer binding to dendrites (De Felice et al., 2007).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as De Felice et al., 2007
Knocking down NMDARs or PrPC, or adding antibodies against their extracellular domains, blocks the accumulation of ADDL clusters at synapses.
“explaining the finding that knocking-down these proteins or adding antibodies against their extracellular domains blocks the accumulation of ADDL clusters (“hotspots”) at synapses (De Felice et al., 2007; Decker et al., 2010a; Lauren et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as De Felice et al., 2007
Excessive Ca++ caused by Aβ oligomers is partially inhibited by NMDA receptor antagonists, including the clinically approved Alzheimer's disease drug Namenda.
“Excessive Ca++ caused by Aβ oligomers is partially inhibited by NMDA-R antagonists, including the clinically approved AD drug Namenda (De Felice et al., 2007).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as De Felice et al., 2007
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- Authors
- De Felice, F. G., Velasco, P. T., Lambert, M. P., Viola, K., Fernandez, S. J., Ferreira, S. T., & Klein, W. L.
- Affiliations
- Northwestern University (US)
- Universidade Federal do Rio de Janeiro (BR)
- Corresponding author
- Klein, William L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-04
- Volume
- 282
- Issue
- 15
- Pages
- 11590-11601
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2053665966
- Cited by
- 882
- References
- 61
- Citations by year
- 2026: 18 · 2025: 34 · 2024: 23 · 2023: 32 · 2022: 33 · 2021: 36 · 2020: 47 · 2019: 55 · 2018: 56 · 2017: 58 · 2016: 46 · 2015: 54 · 2014: 48 · 2013: 57 · 2012: 67
- FWCI
- 35.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- National Institutes of Health (AG11385)
- National Institute on Aging (R01 AG11385, R01AG022547, R01-AG22547, R01AG011385, R01-AG18877, R01AG018877)
- 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
- amyloid-beta oligomers, Alzheimer's disease, oxidative stress, reactive oxygen species, NMDA receptor, NR1 subunit, memantine, NMDA receptor antagonists, hippocampal neurons, synaptosomal membranes, neuroprotection
- MeSH terms
- Animals, Antibodies, Calcium, Cell Differentiation, Hippocampus, Memantine, Neurons, Protein Binding, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, Reactive Oxygen Species, Oxidative Stress, Mice
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