Cholesterol induces oxidative stress and triggers iron and A? accumulation

描述(由申请人提供)：项目摘要/摘要阿尔茨海默病(AD)是一种复杂的神经退行性疾病，目前还没有有效的治疗方法。虽然一些基因突变是导致家族性阿尔茨海默病的原因，但占大多数病例的非家族性阿尔茨海默病的致病因素尚不清楚。因此，确定阿尔茨海默病的危险因素和机制有助于更好地了解该病，并最终可能导致设计一种有效的治疗策略来防止这种破坏性疾病的发生或发展。我们的长期目标是确定危险因素和这些因素触发AD发病的机制。高胆固醇血症是AD的潜在危险因素。然而，高血胆固醇水平影响大脑并增加阿尔茨海默病风险的机制尚不清楚。这项应用的目的是确定高胆固醇饮食在多大程度上导致具有阿尔茨海默病特征的大脑细胞损伤。我们将在兔身上使用长期富含胆固醇的饮食，这是一个我们已经发现的模型系统，可以证明铁沉积、β-淀粉样蛋白(Abeta)积累和氧化应激，这些都是AD的特征。我们的假设是，胆固醇饮食增加了胆固醇代谢产物27-羟基-胆固醇的水平，该代谢产物穿过被破坏的血脑屏障(BBB)并激活内质网应激反应，从而激活生长停滞和DNA损伤诱导基因153(Gadd153)和细胞因子TNF-α。Gadd153的激活触发了活性氧的产生和Abeta的过量产生，而TNF-α的激活改变了铁的代谢，诱导了细胞的凋亡，并加剧了氧化应激。为了验证我们的假设，我们的具体目标如下：目标1.确定高胆固醇血症诱导的氧化应激、Aβ积聚和铁代谢紊乱的机制。我们将确定Gadd153和肿瘤坏死因子-α在铁代谢紊乱、氧化应激诱导和Aβ积累中的作用。目的II.确定铁的螯合作用在多大程度上预防高胆固醇血症的有害影响。我们将确定铁络合剂去铁酮对高胆固醇血症引起的铁代谢紊乱、氧化应激和Abeta生成的影响。目的III.确定降低血胆固醇水平在多大程度上减少27-羟基胆固醇进入大脑，从而抑制氧化应激、铁代谢紊乱和Abeta积聚。我们将比较普伐他汀(一种亲水性他汀类药物，具有低跨越血脑屏障的倾向)和辛伐他汀(一种易于跨越血脑屏障的亲脂性他汀类药物)对氧化应激、铁代谢紊乱和Abeta蓄积的影响。本研究的成功完成可能会揭示高血胆固醇水平与大脑中类似AD的病理之间缺失的联系。

DESCRIPTION (provided by applicant): Project Summary/Abstract Alzheimer's disease (AD) is a complex neurodegenerative disorder for which there is presently no effective therapy. While some genetic mutations are responsible for the familial AD forms, the causative factors for the non-familial forms, which represent the majority of cases, are not known. Identification of risk factors and mechanisms by which these factors contribute to the pathology of AD may therefore aid in better understanding the disease and may ultimately lead to designing an efficient therapeutic strategy to prevent the onset or stop the progression of this devastating disorder. Our longterm objectives are to identify risk factors and mechanisms by which these factors trigger the pathogenesis of AD. Hypercholesterolemia is a potential risk factors for AD. However, the mechanisms by which high blood cholesterol levels affect the brain and increase the risk of AD are not known. The objective of this application is to determine the extent to which cholesterol-enriched diets cause cellular damage in the brain with AD features. We will be using a long-term cholesterol-enriched diet in the rabbits a model system that we have found to demonstrate iron deposition, beta-amyloid (Abeta) accumulation, and oxidative stress, all hallmarks of AD. Our hypothesis is that cholesterol diets increase levels of the cholesterol metabolite, 27-hydroxy-cholesterol, which crosses a disrupted blood brain barrier (BBB) and activates the endoplasmic reticulum stress response, thereby activating the growth arrest-and DNA damage-inducible gene 153 (gadd153) and the cytokine, TNF-alpha. While activation of gadd153 triggers the generation of reactive oxygen species and the overproduction of Abeta, the activation of TNF-alpha alters iron metabolism, induces apoptosis and exacerbates oxidative stress. To test our hypothesis, our specific aims are as follows: Aim I. Identify mechanisms that underlie hypercholesterolemia-induced oxidative stress, Abeta accumulation and iron dyshomeostasis. We will determine the role of gadd153 and TNF-alpha in iron dyshomeostasis, oxidative stress induction and Abeta accumulation. Aim II. Determine the extent to which chelation of iron protects against the deleterious effects of hypercholesterolemia. We will determine the effect of the iron chelator, deferiprone, on hypercholesterolemia-induced iron dyshomeostasis, oxidative stress and Abeta generation. Aim III. Determine the extent to which lowering blood cholesterol levels reduces the entrance of 27- hydroxycholesterol into the brain, thereby inhibiting oxidative stress, iron dyshomeostasis, and Abeta accumulation. We will compare the effects of pravastatin (a hydrophilic statin that has a low propensity to cross the BBB) and simvastatin (a lipophilic statin that readily cross the BBB) on oxidative stress, iron dyshomeostasis, and Abeta accumulation. Successful completion of the present proposal may reveal the missing link between high blood cholesterol levels and AD-like pathology in the brain.