Cholesterol induces oxidative stress and triggers iron and A? accumulation

项目概述/摘要阿尔茨海默病（AD）是一种复杂的神经退行性疾病，目前尚无有效的治疗方法。虽然一些基因突变是家族性AD形式的原因，但非家族性AD形式（占大多数病例）的致病因素尚不清楚。因此，确定导致AD病理的风险因素和机制可能有助于更好地了解该疾病，并可能最终导致设计有效的治疗策略，以预防这种破坏性疾病的发生或阻止其发展。我们的长期目标是确定风险因素和这些因素引发阿尔茨海默病发病机制。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。本应用程序的目的是确定在何种程度上富含胆固醇的饮食导致细胞损伤的大脑与AD的特征。我们将在兔子身上长期使用富含胆固醇的饮食，这是一个模型系统，我们发现铁沉积、β -淀粉样蛋白（Abeta）积累和氧化应激，这些都是阿尔茨海默病的特征。我们的假设是，胆固醇饮食增加了胆固醇代谢物27-羟基胆固醇的水平，27-羟基胆固醇穿过被破坏的血脑屏障（BBB），激活内质网应激反应，从而激活生长阻滞和DNA损伤诱导基因153 （gadd153）和细胞因子tnf - α。gadd153的激活会触发活性氧的产生和β的过量产生，而tnf - α的激活会改变铁代谢，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：目的一：确定高胆固醇血症诱导的氧化应激、β积累和铁代谢失衡的机制。我们将确定gadd153和tnf - α在铁平衡失调、氧化应激诱导和β积累中的作用。目的二世。确定铁螯合对高胆固醇血症有害影响的保护程度。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失调、氧化应激和β生成的影响。第三目标。确定降低血胆固醇水平可在多大程度上减少27-羟基胆固醇进入大脑，从而抑制氧化应激、铁代谢失调和β积累。我们将比较普伐他汀（一种低倾向穿过血脑屏障的亲水性他汀类药物）和辛伐他汀（一种容易穿过血脑屏障的亲脂性他汀类药物）对氧化应激、铁代谢失调和β积累的影响。本研究的成功完成可能会揭示高血胆固醇水平与大脑ad样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.