TY - JOUR
T1 - Prolonged exposure of cortical neurons to oligomeric amyloid-β impairs NMDA receptor function via NADPH oxidasemediated ROS production
T2 - Protective effect of green tea (-)-epigallocatechin-3-gallate
AU - He, Yan
AU - Cui, Jiankun
AU - Lee, James C.m.
AU - Ding, Shinghua
AU - Chalimoniuk, Malgorzata
AU - Simonyi, Agnes
AU - Sun, Albert Y.
AU - Gu, Zezong
AU - Weisman, Gary A.
AU - Gibson Wood, W.
AU - Sun, Grace Y.
PY - 2011
Y1 - 2011
N2 - 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 Ab 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, Abinduced 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 oxidasemediated 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.
AB - 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 Ab 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, Abinduced 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 oxidasemediated 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.
KW - (2)-epigallocatechin-3-gallate (EGCG)
KW - Arachidonic acid (AA) release
KW - Ca influx
KW - N-methyl-D-aspartate (NMDA) receptor
KW - NADPH oxidase
KW - Oligomeric Aβ
KW - Reactive oxygen species (ROS)
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U2 - 10.1042/AN20100025
DO - 10.1042/AN20100025
M3 - Article
C2 - 21434871
AN - SCOPUS:79952375934
SN - 1759-0914
VL - 3
SP - 13
EP - 24
JO - ASN Neuro
JF - ASN Neuro
IS - 1
M1 - e00050
ER -