RGD Reference Report - Abeta 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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Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine.
Authors:	De Felice, Fernanda G Velasco, Pauline T Lambert, Mary P Viola, Kirsten Fernandez, Sara J Ferreira, Sergio T Klein, William L
Citation:	De Felice FG, etal., J Biol Chem. 2007 Apr 13;282(15):11590-601. Epub 2007 Feb 16.
RGD ID:	12910994
Pubmed:	PMID:17308309 (View Abstract at PubMed)
DOI:	DOI:10.1074/jbc.M607483200 (Journal Full-text)
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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Biological Process

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Grin1	Rat	positive regulation of calcium ion transport into cytosol	involved_in	IGI	ComplexPortal:CPX-1134	PMID:17308309	ARUK-UCL
Grin1	Rat	positive regulation of reactive oxygen species biosynthetic process	involved_in	IGI	ComplexPortal:CPX-1134	PMID:17308309	ARUK-UCL

Cellular Component

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Grin1	Rat	synaptic membrane	located_in	IPI	ComplexPortal:CPX-1134	PMID:17308309	ARUK-UCL

Molecular Function

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Grin1	Rat	amyloid-beta binding	enables	IDA		PMID:17308309	ARUK-UCL
Grin1	Rat	protein-containing complex binding	enables	IPI	ComplexPortal:CPX-1134	PMID:17308309	ARUK-UCL

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Genes (Rattus norvegicus)

Grin1 (glutamate ionotropic receptor NMDA type subunit 1)

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Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine.