Journal
ASN NEURO
Volume 3, Issue 1, Pages 13-24Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1042/AN20100025
Keywords
arachidonic acid (AA) release; Ca2+ influx; (-)-epigallocatechin-3-gallate (EGCG); NADPH oxidase; N-methyl-D-aspartate (NMDA) receptor; oligomeric A beta; reactive oxygen species (ROS)
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Funding
- National Institute of Aging [2P01 AG018357]
- National Center for Complementary and Alternative Medicines of the National Institutes of Health [1P50 AT006273]
- NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE [P50AT006273] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG018357] Funding Source: NIH RePORTER
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Excessive production of A beta (amyloid beta-peptide) has been shown to play an important role in the pathogenesis of AD (Alzheimer's disease). Although not yet well understood, aggregation of A beta is known to cause toxicity to neurons. Our recent study demonstrated the ability for oligomeric A beta 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 A beta 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 A beta 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 A beta 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 A beta-induced ROS production. Furthermore, A beta-induced mitochondrial dysfunction, impairment of NMDA Ca2+ influx and ROS production were prevented by pretreatment of neurons with EGCG [(2)-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 A beta, and demonstrate the therapeutic potential of EGCG and other dietary polyphenols in delaying onset or retarding the progression of AD.
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