Amyloid-beta toxicity in neurons and potential botanical compounds for prevention of Alzheimer's disease
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Alzheimer's disease (AD) is characterized by a progressive decline in memory and cognitive function together with increased oxidative stress in the brain. Although there is increasing evidence indicating the involvement of oligomeric amyloid-beta peptides (Aβ) in mediating oxidative damage to neurons, the mechanism(s) about how these peptides alter neuronal functions remains elusive. Recent studies from our laboratory have demonstrated the effects of N-methyl-D-aspartic acid (NMDA) and oligomeric Aβ to produce reactive oxygen species (ROS) from NADPH oxidase, and stimulate downstream signaling pathways leading to activation of mitogen-activated protein kinases (MAPKs) and cytosolic phospholipase A2 (cPLA2) in neurons. In this study, we investigated the effects of prolonged exposure of neurons to oligomeric Aβ and their response to NMDA-induced Ca2+ influx, release of arachidonic acid (AA), mitochondrial dysfunction, and ROS production. Results demonstrated that prolonged exposure of neurons to Aβ caused mitochondrial dysfunction, a decrease in NMDA-induced Ca2+ influx and AA release, and an increase in levels of ROS. Neuronal impairments induced by Aβ could be blocked by gp91ds-tat, a specific inhibitor for NADPH oxidase as well as other ROS scavengers, including the botanical phenolic compound, epigallochatechin-gallate (EGCG) from green tea. These studies thus identified the involvement of NADPH oxidase as a source of ROS in the cytotoxic effects of Aβ. These results also provide a neuron model for identifying novel botanical antioxidants to protect against neurotoxic effects of Aβ oligomers.
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