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。我们将在兔子身上使用长期的高胆固醇饮食，我们已经发现了一个模型系统，可以证明铁沉积-淀粉样蛋白(A？)积聚和氧化应激，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-？Gadd153的激活触发了活性氧的产生和A？的过量产生，而TNF-？的激活则触发了A？改变铁代谢，诱导细胞凋亡，加剧氧化应激。为了验证我们的假设，我们的具体目标如下：目标I.确定高胆固醇血症诱导氧化应激的基础机制，A？蓄积和铁代谢紊乱。我们将确定Gadd153和肿瘤坏死因子？在铁代谢紊乱中，氧化应激诱导和A？积累。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A？一代。目的III.确定降低血胆固醇水平在多大程度上减少了27-羟基胆固醇进入大脑，从而抑制氧化应激、铁代谢紊乱和A？积累。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A？积累。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。公共卫生相关性：项目叙述高胆固醇血症在美国是一个严重的健康问题，除了心血管问题外，还可能增加阿尔茨海默病的风险。然而，高血胆固醇水平导致AD病理的机制尚不清楚。这一建议的结果可能有助于更好地理解血液中高胆固醇水平导致AD变性的机制，并最终可能有助于设计预防或减缓这种破坏性神经退行性疾病的高胆固醇相关形式的进展的策略。

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, ?-amyloid (A?) 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-?. While activation of gadd153 triggers the generation of reactive oxygen species and the overproduction of A?, the activation of TNF-? 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, A? accumulation and iron dyshomeostasis. We will determine the role of gadd153 and TNF-? in iron dyshomeostasis, oxidative stress induction and A? 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 A? 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 A? 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 A? accumulation. Successful completion of the present proposal may reveal the missing link between high blood cholesterol levels and AD-like pathology in the brain. PUBLIC HEALTH RELEVANCE: Project narrative Hypercholesterolemia is a serious health issue in the U.S.A. which, in addition to cardiovascular problems, may also increase the risk for Alzheimer's disease. However, the mechanisms by which high blood cholesterol levels cause AD pathology are not known. The outcome of this proposal may aid in a better understanding of the mechanisms by which high cholesterol levels in blood cause degeneration characteristic of AD, and may ultimately help in designing strategies that prevent or slow the progression of hypercholesterolemia-related forms of this devastating neurodegenerative disorder.