Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine*

By F. D. De Felice, P. Velasco, M. Lambert, K. Viola, Sara J. Fernandez, Sérgio T. Ferreira, W. Klein. Journal of Biological Chemistry, 2007

904 citations recorded by the source corpus.

Oxidative stress is a major aspect of Alzheimer disease (AD) pathology. We have investigated the relationship between oxidative stress and neuronal binding of Aβ 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.

Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/3c3c4ef390a38474624510bec9d99733435947ea

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Citations in the corpus

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “oAβ may directly interact with NMDAR, as NMDAR subunits can co-immunoprecipitate with oAβ [63].”
Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers (2009, methodology): “We recently showed that ADDLs induce oxidative stress in hippocampal neurons (16), thus establishing a connection between the neuronal impact of ADDLs and a major AD neuropathology.”
Aβ Oligomers Cause Localized Ca2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines (2010, background): “4e,f), and involving NMDA receptors and others (De Felice et al., 2007; Shankar et al., 2007).”
Oxidative Stress and the Pathogenesis of Alzheimer's Disease (2013, background): “…and MCI brains, the increased oxidative damage to lipids and proteins and the decline of glutathione and antioxidant enzyme activities are more localized to the synapses and correlate with the severity of the disease, suggesting an involvement of oxidative stress in AD-related synaptic loss [21].”
Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease (2014, background): “In AD, aberrant stimulation of excitatory N-methyl-D-aspartate receptors (NMDA-Rs) by AbOs has been proposed as a key mechanism leading to excessive ROS production, likely as a consequence of Ca-related mitochondrial dysfunction (130).”
Role of glutamate and NMDA receptors in Alzheimer’s disease (2016, neutral): “A (cid:2) may even physically interact with NMDARs, either directly or via synaptic proteins such as PSD95 [51–53].”
Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system--too little activation is bad, too much is even worse. (2007, background): “Similarly, memantine (5 or 10 mM) prevented oxidative stress and calcium influx produced by Aß oligomers in hippocampal neuronal cultures (De Felice et al., 2007a).”
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade (2018, background): “A O-associated NMDAR activation [62] promotes Ca++ release from the ER, which leads”