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，目前没有有效的治疗方法。虽然一些基因突变是导致家族性AD形式的原因，但代表大多数病例的非家族性形式的致病因素尚不清楚。因此，识别风险因素和机制，这些因素有助于AD的病理学可能有助于更好地了解疾病，并可能最终导致设计一种有效的治疗策略，以防止这种破坏性疾病的发作或停止其进展。我们的长期目标是确定风险因素和机制，这些因素触发的发病机制，AD。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AD风险的机制尚不清楚。本申请的目的是确定富含胆固醇的饮食对具有AD特征的大脑造成细胞损伤的程度。我们将在兔子中使用长期富含胆固醇的饮食，我们发现该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的标志。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，27-羟基胆固醇穿过破坏的血脑屏障（BBB）并激活内质网应激反应，从而激活生长抑制和DNA损伤诱导基因153（gadd 153）和细胞因子TNF-α。虽然gadd 153的激活触发活性氧簇的产生和Abeta的过量产生，但TNF-α的激活改变铁代谢，诱导细胞凋亡并加剧氧化应激。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的氧化应激，Abeta积累和铁稳态失调的机制。我们将确定gadd 153和TNF-α在铁稳态异常、氧化应激诱导和Abeta积累中的作用。Aim II.确定铁螯合作用对高胆固醇血症有害作用的保护程度。我们将确定铁螯合剂去铁酮对高胆固醇血症诱导的铁稳态异常、氧化应激和Abeta生成的影响。Aim III.确定降低血液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，铁稳态失调和Abeta积累。我们将比较普伐他汀（一种亲水性他汀类药物，穿过血脑屏障的倾向较低）和辛伐他汀（一种亲脂性他汀类药物，易于穿过血脑屏障）对氧化应激、铁稳态异常和Abeta蓄积的影响。本提案的成功完成可能会揭示高血胆固醇水平和大脑中AD样病理学之间的缺失联系。

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.