title: Prolonged exposure of cortical neurons to oligomeric amyloid-β impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (-)-epigallocatechin-3-gallate.
abstract: Excessive production of Aβ (amyloid β-peptide) has been shown to play an important role in the pathogenesis of AD (Alzheimer's disease). Although not yet well understood, aggregation of Aβ is known to cause toxicity to neurons. Our recent study demonstrated the ability for oligomeric Aβ to stimulate the production of ROS (reactive oxygen species) in neurons through an NMDA (N-methyl-D-aspartate)-dependent pathway. However, whether prolonged exposure of neurons to aggregated Aβ is associated with impairment of NMDA receptor function has not been extensively investigated. In the present study, we show that prolonged exposure of primary cortical neurons to Aβ oligomers caused mitochondrial dysfunction, an attenuation of NMDA receptor-mediated Ca2+ influx and inhibition of NMDA-induced AA (arachidonic acid) release. Mitochondrial dysfunction and the decrease in NMDA receptor activity due to oligomeric Aβ are associated with an increase in ROS production. Gp91ds-tat, a specific peptide inhibitor of NADPH oxidase, and Mn(III)-tetrakis(4-benzoic acid)-porphyrin chloride, an ROS scavenger, effectively abrogated Aβ-induced ROS production. Furthermore, Aβ-induced mitochondrial dysfunction, impairment of NMDA Ca2+ influx and ROS production were prevented by pre-treatment of neurons with EGCG [(-)-epigallocatechin-3-gallate], a major polyphenolic component of green tea. Taken together, these results support a role for NADPH oxidase-mediated ROS production in the cytotoxic effects of Aβ, and demonstrate the therapeutic potential of EGCG and other dietary polyphenols in delaying onset or retarding the progression of AD.
authors: Department of Biochemistry, University of Missouri, Columbia, MO, USA.
authors: Yan
authors: Y
authors: He
authors: Jiankun
authors: J
authors: Cui
authors: James C-M
authors: JC
authors: Lee
authors: Shinghua
authors: S
authors: Ding
authors: Malgorzata
authors: M
authors: Chalimoniuk
authors: Agnes
authors: A
authors: Simonyi
authors: Albert Y
authors: AY
authors: Sun
authors: Zezong
authors: Z
authors: Gu
authors: Gary A
authors: GA
authors: Weisman
authors: W Gibson
authors: WG
authors: Wood
authors: Grace Y
authors: GY
authors: Sun
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004347:Drug Interactions; D004622:Embryo, Mammalian; D006023:Glycoproteins / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010078:Oxazines; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014966:Xanthenes
chemical_list: D016229:Amyloid beta-Peptides; D006023:Glycoproteins; D018696:Neuroprotective Agents; D010078:Oxazines; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D013778:Tetrazolium Salts; D013844:Thiazoles; D014966:Xanthenes; C075222:amyloid beta-protein (1-42); C473031:gp91ds-tat protein, chimeric; C005843:resazurin; D016718:Arachidonic Acid; D016202:N-Methylaspartate; D002392:Catechin; C045651:epigallocatechin gallate; D007770:L-Lactate Dehydrogenase; D019255:NADPH Oxidases; C022616:thiazolyl blue; D002118:Calcium