Do proteomics analyses provide insights into reduced oxidative stress in the brain of an Alzheimer disease transgenic mouse model with an M631L amyloid precursor protein substitution and thereby the importance of amyloid-beta-resident methionine 35 in Alzheimer disease pathogenesis?

The single methionine (Met/M) residue of amyloid-beta (Aβ) peptide, at position 35 of the 42-mer, has important relevance for Aβ-induced oxidative stress and neurotoxicity. Recent in vivo brain studies in a transgenic (Tg) Alzheimer disease (AD) mouse model with Swedish and Indiana familial AD mutations in human amyloid precursor protein (APP) (referred to as the J20 Tg mouse) demonstrated increased levels of oxidative stress. However, the substitution of the Met631 residue of APP to leucine (Leu/L) (M631L in human APP numbering, referred to as M631L Tg and corresponding to residue 35 of Aβ1-42) resulted in no significant in vivo oxidative stress levels, thereby supporting the hypothesis that Met-35 of Aβ contributes to oxidative insult in the AD brain. It is conceivable that oxidative stress mediated by Met-35 of Aβ is important in regulating numerous downstream effects, leading to differential levels of relevant biochemical pathways in AD. Therefore, in the current study using proteomics, we tested the hypothesis that several brain proteins involved in pathways such as energy and metabolism, antioxidant activity, proteasome degradation, and pH regulation are altered in J20Tg versus M631L Tg AD mice.

淀粉样β（Aβ）肽42聚体第35位的单个甲硫氨酸（Met/M）残基对Aβ诱导的氧化应激和神经毒性具有重要意义。最近在一种转基因（Tg）阿尔茨海默病（AD）小鼠模型中的体内脑部研究表明，该小鼠模型携带人淀粉样前体蛋白（APP）的瑞典和印第安纳家族性AD突变（称为J20 Tg小鼠），其氧化应激水平升高。然而，将APP的Met631残基替换为亮氨酸（Leu/L）（人APP编号中的M631L，称为M631L Tg，对应于Aβ1 - 42的第35位残基），体内氧化应激水平无显著变化，从而支持了Aβ的Met - 35导致AD大脑氧化损伤这一假说。可以想象，由Aβ的Met - 35介导的氧化应激在调节众多下游效应方面很重要，导致AD中相关生化途径的水平存在差异。因此，在当前利用蛋白质组学进行的研究中，我们检验了这样一个假说：在J20 Tg与M631L Tg AD小鼠中，参与能量和代谢、抗氧化活性、蛋白酶体降解以及pH调节等途径的几种脑蛋白发生了改变。