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J. Biol. Chem., Vol. 282, Issue 15, 11590-11601, April 13, 2007

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

Fernanda G. De Felice¹, Pauline T. Velasco, Mary P. Lambert, Kirsten Viola, Sara J. Fernandez, Sergio T. Ferreira², and William L. Klein³

From the Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208 and the Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil

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

Received for publication, August 7, 2006 , and in revised form, February 15, 2007.

^* This work was supported by grants from the Alzheimer's Disease Research Fund and NIA, National Institutes of Health, Grants RO1-AG18877, RO1-AG22547, and RO1-AG11385. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ A Human Frontier Science Program Fellow and supported by a grant from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq/Brazil).

² A Howard Hughes Medical Institute International Scholar. To whom correspondence may be addressed. Tel.: 5521-2562-6790; E-mail: ferreira{at}bioqmed.ufrj.br.

³ To whom correspondence may be addressed. Tel.: 847-491-2868; E-mail: wklein{at}northwestern.edu.

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