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 (Abeta) levels and Abeta plaques from 3 months. We tested if enhancing oxidative stress through diet would accelerate Abeta-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 Abeta in the cortex of TASTPM but did not alter Abeta 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 Abeta 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.