Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
Neurobiol Aging. 2012 May;33(5):960-8. doi: 10.1016/j.neurobiolaging.2010.07.008. Epub 2010 Aug 17.
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 (Aβ) levels and Aβ plaques from 3 months. We tested if enhancing oxidative stress through diet would accelerate Aβ-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 Aβ in the cortex of TASTPM but did not alter Aβ plaque load, presenilin 1, or β-secretase (BACE1) expression. TASTPM cortical neurons were cultured under similar pro-oxidant conditions resulting in increased levels of APP and Aβ likely as a result of enhanced β/γ 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.
阿尔茨海默病（AD）的病因复杂，氧化应激可能是发病机制和疾病进展的一个促成因素。表达家族性 AD 相关淀粉样前体蛋白（APPswe）和早老素转基因（PS1M146V）的 TASTPM 转基因小鼠从 3 个月起大脑中淀粉样β（Aβ）水平和 Aβ斑块增加。我们测试了通过饮食增强氧化应激是否会加速 Aβ相关的病理变化。TASTPM 喂食促氧化剂饮食 3 个月，导致大脑蛋白羰基水平升高、Nrf2 升高和谷胱甘肽（GSH）浓度升高。这种饮食增加了 TASTPM 皮质中的淀粉样前体蛋白（APP）和 Aβ，但没有改变 Aβ斑块负荷、早老素 1 或β-分泌酶（BACE1）的表达。TASTPM 皮质神经元在类似的促氧化剂条件下培养，导致 APP 和 Aβ水平升高，可能是由于 APP 的β/γ 分泌酶加工增强所致。因此，促氧化剂条件会增加 APP 水平，并增强 BACE1 介导的 APP 加工，从而有助于 AD 的发病机制。
