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，淀粉样蛋白（A？）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-？。虽然gadd 153的激活触发了活性氧的产生和A？的过量产生，TNF-？改变铁代谢、诱导细胞凋亡和加重氧化应激。为了验证我们的假设，我们的具体目标如下：目标I。确定机制，高胆固醇血症诱导的氧化应激，A？铁积累和铁稳态失调。我们将确定gadd 153和TNF-α的作用？在铁稳态异常，氧化应激诱导和A？积累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，对高胆固醇血症引起的铁代谢紊乱，氧化应激和A？一代Aim III.确定在何种程度上降低血液胆固醇水平减少27-羟基胆固醇进入大脑，从而抑制氧化应激，铁代谢障碍，和A？积累我们将比较普伐他汀（一种亲水性他汀类药物，具有较低的倾向，通过血脑屏障）和辛伐他汀（一种亲脂性他汀类药物，很容易通过血脑屏障）对氧化应激，铁代谢紊乱，和A？积累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。公共卫生相关性：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，高血胆固醇水平引起AD病理学的机制尚不清楚。这项建议的结果可能有助于更好地了解血液中高胆固醇水平导致AD变性特征的机制，并最终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血症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.