Oxidative lipid stress in the brain

描述(申请人提供)：氧化应激似乎与阿尔茨海默病的发病机制有关，最可能涉及A？蛋白质和多不饱和脂肪酸(PUFA)链。因此，我们建议(1)确定A的表达是否？蛋白质增加大脑中氧化多不饱和脂肪酸代谢和降解的速率，以及在大脑易患疾病和抵抗疾病的区域是否有不同的速率；(2)测试A？一般情况下，蛋白质通过脂类氧化产物增加蛋白质修饰，A？在体内，蛋白质被加速聚集成淀粉样纤维的脂氧化产物修饰；以及(3)测试特定的饮食和药物干预措施是否改变易患疾病的大脑区域有毒多不饱和脂肪酸降解产物的产生，或这些区域多不饱和脂肪酸降解产物的命运。我们将利用放射性标记的多不饱和脂肪酸链，将其注射到阿尔茨海默病转基因小鼠模型中，以及定量和测序质谱学。

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.