Pro-oxidant diet enhances β/γ secretase-mediated APP processing in APP/PS1 transgenic mice

The etiology of Alzheimer's disease (AD) is complex with oxidative stress being a possible contributory factor to pathogenesis and disease progression. TASTPM transgenic mice expressing familial AD-associated amyloid precursor protein (APPswe) and presenilin transgenes (PS1M146V) show increased brain amyloid beta (A beta) levels and A beta plaques from 3 months. We tested if enhancing oxidative stress through diet would accelerate A beta-related pathology. TASTPM were fed a pro-oxidant diet for 3 months resulting in increased brain levels of protein carbonyls, increased Nrf2, and elevated concentrations of glutathione (GSH). The diet increased both amyloid precursor protein (APP) and A beta in the cortex of TASTPM but did not alter A beta plaque load, presenilin 1, or beta-secretase (BACE1) expression. TASTPM cortical neurons were cultured under similar pro-oxidant conditions resulting in increased levels of APP and A beta likely as a result of enhanced beta/gamma secretase processing of APP. Thus, pro-oxidant conditions increase APP levels and enhance BACE1-mediated APP processing and in doing so might contribute to pathogenesis in AD. (C) 2012 Elsevier Inc. All rights reserved.