Cholesterol and brain injury-induced Abeta

胆固醇和脑损伤引起的 Abeta

• 批准号: 7314586
• 负责人: MARK P BURNS
• 金额: $ 7.76万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314586
• 关键词: Abeta synthesis; Acute; Agonist; Alzheimer' s Disease; American; Amyloid beta-Protein; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Apolipoproteins; Apoptotic; Area; Autopsy; Behavioral; Brain; Brain Injuries; Cell Death; Cell Surface Receptors; Cell membrane; Cell surface; Cells; Centers for Disease Control and Prevention (U.S.); Cholesterol; Cholesterol Homeostasis; Cleaved cell; Contralateral; Data; Deposition; Development; Elements; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Event; Future; High Density Lipoprotein Cholesterol; Hospitalization; Hour; Human; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro; Incidence; Injury; Interleukin-1; Interleukin-6; Ipsilateral; LDL-Receptor Related Protein 1; Lead; Lesion; Life; Link; Lipoprotein Receptor; Lovastatin; Low Density Lipoprotein Receptor; Measures; Membrane; Membrane Lipids; Modeling; Movement; Mus; Neurons; Neurotoxins; Numbers; Pathology; Pathway interactions; Peptides; Peripheral; Pharmaceutical Preparations; Plasma; Production; Protein Precursors; Proteins; Rattus; Recycling; Reporting; Research; Risk Factors; Rodent; Role; Staining method; Stains; System; TNF gene; Testing; Therapeutic Intervention; Traumatic Brain Injury; abstracting; base; brain cell; cell injury; cell killing; cell type; cholesterol transporters; cognitive recovery; cost; day; design; disability; drug development; genetic regulatory protein; in vivo; injured; mouse model; multidisciplinary; neuron loss; neurotoxic; novel strategies; peptide A; prevent; response; size; therapeutic target; therapy development

DESCRIPTION (provided by applicant): Abstract Brain trauma in humans may be a significant risk factor in developing Alzheimer's disease. A number of studies have shown the presence of A-beta plaques in postmortem brains of single-incidence brain trauma victims. A-beta is neurotoxic peptide that forms the plaques that are the major pathology in Alzheimer's disease. The production and accumulation of A-beta may be responsible for neuronal cell loss that occurs in the hours and days following brain trauma. However, why the production of A-beta increases following brain trauma is not yet known. By using animal models of brain trauma we can elucidate mechanisms involved in A-beta production, as well as understanding pathways involved in neuronal cell death following brain trauma. A-beta is formed when a transmembrane precursor protein is cleaved. Cholesterol is an integral membrane lipid and is found in high concentrations in the brain. In vitro, when cellular cholesterol levels increase, cleavage of the precursor protein to A-beta also increases. A decrease in cholesterol levels causes a decrease in A-beta formation. These results have been replicated with cholesterol lowering drugs in vivo. In humans, taking cholesterol lowering drugs may reduce the incidence of Alzheimer's disease. Traumatic brain trauma in rodents causes a chain of cell death, starting in the region of direct impact. As the cells die and degrade, their constituent parts are recycled. We hypothesize that this leads to a transient increase in cholesterol levels in cells immediately surrounding the injured area, and this increase is responsible for the acute increase in A-beta levels following brain trauma. We aim to test this hypothesis by 1) Measuring cholesterol-related regulatory proteins and the A-beta response following brain trauma in rodents and 2) attempting to intervene and inhibit these changes by using an LXR agonist (TO-901317) and a statin (lovastatin) prior to and following injury. We believe that TO-901317 will prevent cells surrounding the injured area from accepting cholesterol from damaged neurons, and that this will prevent the TBI-induced A-beta spike. Statins have previously been shown to be beneficial in cognitive recovery and lesion size following TBI, therefore we will examine the effects of lovastatin on both the cholesterol response to TBI, and its anti-inflammatory effects in an attempt to elucidate a possible mechanism of action. These studies aim to understand how A-beta is produced, and why brain injury can lead to production of the neurotoxin, A-beta Project Relevance This research aims to investigate how cholesterol homeostasis is altered following traumatic brain injury (TBI) in mice, and if this change in cholesterol is responsible for the increased production of Abeta that has been reported in this model. As CNS cholesterol is independent of fluctuations in peripheral cholesterol, it is difficult to examine the effects of cholesterol in the CNS independent of effects in the periphery. Using TBI as a model of dysfunctional intracerebral cholesterol homeostasis is a novel approach to examine how changes in CNS cholesterol alone can alter Abeta levels. Furthermore, the data we provide in this project will help determine the course of events following TBI, and the pathways identified may help guide future drug development studies. As such this project has multidisciplinary benefits and is relevant to the fields of CNS cholesterol, Alzheimer's disease and brain injury.

描述（由申请人提供）：摘要人类脑创伤可能是发展阿尔茨海默病的重要危险因素。许多研究表明，在单次脑外伤受害者的死后大脑中存在A-β斑块。A-β是一种神经毒性肽，它形成的斑块是阿尔茨海默病的主要病理。A-β的产生和积累可能是脑创伤后数小时和数天内发生的神经元细胞损失的原因。然而，为什么脑外伤后A-β的产生增加还不清楚。通过使用脑创伤动物模型，我们可以阐明A-β产生的机制，并了解脑创伤后神经元细胞死亡的途径。当跨膜前体蛋白被切割时形成A-β。胆固醇是一种不可或缺的膜脂质，在大脑中浓度很高。在体外，当细胞胆固醇水平增加时，前体蛋白向A-β的裂解也增加。胆固醇水平的降低会导致A-β形成的减少。这些结果已经在体内用降胆固醇药物复制。在人类中，服用降低胆固醇的药物可能会降低阿尔茨海默病的发病率。啮齿类动物的创伤性脑损伤导致细胞死亡链，从直接影响的区域开始。随着细胞死亡和降解，它们的组成部分被回收利用。我们假设，这会导致受伤区域周围细胞中胆固醇水平的短暂增加，这种增加是脑创伤后A-β水平急性增加的原因。我们的目的是通过1）测量啮齿动物脑创伤后胆固醇相关的调节蛋白和A-β反应，2）在损伤前后使用LXR激动剂（TO-901317）和他汀类药物（洛伐他汀）试图干预和抑制这些变化来验证这一假设。我们相信TO-901317将阻止损伤区域周围的细胞接受来自受损神经元的胆固醇，这将阻止TBI诱导的A-β峰。他汀类药物以前已被证明是有益的认知恢复和损伤的大小TBI后，因此，我们将检查洛伐他汀的胆固醇对TBI的反应，其抗炎作用，试图阐明一个可能的作用机制。这些研究旨在了解A-β是如何产生的，以及为什么脑损伤会导致神经毒素的产生，A-β项目相关性这项研究旨在研究小鼠创伤性脑损伤（TBI）后胆固醇体内平衡如何改变，以及胆固醇的这种变化是否导致该模型中报告的Abeta产生增加。由于CNS胆固醇不受外周胆固醇波动的影响，因此很难独立于外周胆固醇的影响来检查CNS中胆固醇的影响。使用TBI作为功能失调的脑内胆固醇稳态的模型是一种新的方法来检查中枢神经系统胆固醇的变化如何单独改变Abeta水平。此外，我们在该项目中提供的数据将有助于确定TBI后的事件过程，所确定的途径可能有助于指导未来的药物开发研究。因此，该项目具有多学科的益处，并且与CNS胆固醇、阿尔茨海默病和脑损伤领域相关。