Oxidative lipid stress in the brain

描述（由申请人提供）：氧化应激似乎参与了阿尔茨海默病的发病机制，并且最有可能涉及A？蛋白质和多不饱和脂肪酸（PUFA）链。因此，我们建议(1)确定A？蛋白质增加大脑中氧化PUFA代谢和降解的速度，以及大脑易发和抗病区域的速率是否不同；(2)测试A？一般来说，脂质氧化产物会增加蛋白质修饰，而A？蛋白质在体内被脂质氧化产物修饰，加速其聚集成淀粉样原纤维；(3)测试特定的饮食和药物干预是否会改变易发疾病大脑区域有毒PUFA降解产物的产生，或者这些区域PUFA降解产物的命运。我们将利用放射性标记的PUFA链，将其注射到阿尔茨海默病的转基因小鼠模型中，以及定量和测序质谱。

DESCRIPTION (provided by applicant): Oxidative stress appears to be involved in the pathogenesis of Alzheimer's disease, and most likely involves interactions between A? proteins and polyunsaturated fatty acyl (PUFA) chains. Therefore, we are proposing to (1) determine whether the expression of A? proteins increases the rate of oxidative PUFA metabolism and degradation in brain, and whether the rates differ in disease-prone and disease-resistant regions of brain; (2) test whether A? proteins increase protein modification by lipid oxidation products in general, and whether A? proteins are modified in vivo by the lipid oxidation products that accelerate their aggregation into amyloid fibrils; and (3) test whether specific dietary and pharmacological interventions alter the production of toxic PUFA degradation products in disease-prone brain regions, or the fate of PUFA degradation products in these regions. We will make use of radiolabeled PUFA chains, which will be injected into transgenic mouse models of Alzheimer's disease, as well as quantitative and sequencing mass spectrometry.