Amyloid-beta toxicity in neurons and potential botanical compounds for prevention of Alzheimer's disease

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] 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 (A[beta]) 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 A[beta] 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 A[beta] 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 A[beta] caused mitochondrial dysfunction, a decrease in NMDA-induced Ca2+ influx and AA release, and an increase in levels of ROS. Neuronal impairments induced by A[beta] 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 A[beta]. These results also provide a neuron model for identifying novel botanical antioxidants to protect against neurotoxic effects of A[beta] oligomers.