Article

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

Northwestern University, Evanston, Illinois, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2007; 282(15):11590-601. DOI: 10.1074/jbc.M607483200
Source: PubMed

ABSTRACT

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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    • "Interference with Aβ-HSPG binding via treatment with heparin or heparinase can mitigate these toxic effects of Aβ monomeric forms of Aβ (Aβ 1-40 and Aβ 1-42 ) on one vascular cell type (VSMC), our results may well have mechanistic implications on other forms of Aβ-induced CV dysfunction including that caused by vascular endothelial cell (VEC) dysfunction and that caused by higher order Aβ species. Support for the former comes from in vitro, ex vivo, and in vivo studies that implicate ROS in Aβinduced VEC dysfunction[13,17,57]and VEC-mediated vasomotor impairment;[13,17,575859support for the latter comes from in vitro and in vivo studies demonstrating that oligomeric Aβ (at least in neurons)[60]and fibrillar Aβ (in cerebral vessels and neurons)[18,6162636465cause even greater degrees of oxidative stress. Therefore, while elevated levels of soluble Aβ—and their attendant vascular consequences including altered CV reactivity[6]and impaired CBF[49,50]—are present in the early stages of AD when fibrillar Aβ in the form of neuritic plaques and CAA have yet to develop to a significant degree, the mechanisms elucidated in our study may very well exert their greatest impact on the later stages of AD when higher order Aβ species are much more abundant . "
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    • "The trimer Ab oligomers can also contribute to the neuronal toxicity, albeit at a lower level compared to tetrameric Ab. The presence of trimeric and tetrameric but not dimeric species in the ADDLS preparations, which are highly toxic (Gong et al. 2003;De Felice et al. 2007) supports our model. As the trimer and tetramer oligomeric Ab species are highly toxic to neurons in culture, we need to determine the toxicity of purified Ab trimer and tetramer in vivo. "
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