Interplay Between Hippocampal Glutathione Depletion and pH Increment in Alzheimer’s Disease

Oxidative stress (OS) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Elevated OS in AD lowers the level of glutathione (GSH), a brain antioxidant. Currently, GSH is under examination in the clinical population for understanding its association with oxidative load in AD research. Significant depletion in hippocampal GSH, as observed using in vivo magnetic resonance spectroscopy (MRS), reportedly correlates with cognitive impairment in AD. Alterations in cellular-energy metabolism and increased hippocampal pH have also been reported in AD. Hence, this combined molecular interplay between hippocampal GSH and pH must be studied longitudinally for advancing AD research. Herein, we propose a schematic model depicting the molecular events in AD pathogenesis and provide a possible link between OS, GSH depletion, and pH alterations in the hippocampus. The model would further potentiate the need for in vivo longitudinal studies to confirm the interlinked mechanism between OS, hippocampal GSH depletion, and pH increment in an AD patient brain.