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）：摘要人类脑外伤可能是患阿尔茨海默病的一个重要危险因素。许多研究表明，单次脑外伤受害者死后大脑中存在 A-β 斑块。 A-β 是一种神经毒性肽，可形成斑块，而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外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 的产生会增加尚不清楚。通过使用脑外伤的动物模型，我们可以阐明 A-β 产生的机制，并了解脑外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。胆固醇是一种完整的膜脂，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 的裂解也会增加。胆固醇水平降低会导致 A-β 形成减少。这些结果已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。啮齿动物的脑外伤会导致一系列细胞死亡，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。我们推测，这会导致受伤区域周围细胞中胆固醇水平短暂升高，而这种升高是脑外伤后 A-β 水平急剧升高的原因。我们的目标是通过 1) 测量啮齿类动物脑损伤后胆固醇相关调节蛋白和 A-β 反应来检验这一假设，2) 尝试使用 LXR 激动剂 (TO-901317) 和他汀类药物 (TO-901317) 干预和抑制这些变化。洛伐他汀）在受伤之前和之后。我们相信 TO-901317 将阻止受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 峰值。他汀类药物先前已被证明对 TBI 后的认知恢复和病变大小有益，因此我们将研究洛伐他汀对 TBI 胆固醇反应及其抗炎作用的影响，以试图阐明可能的作用机制。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 项目相关性本研究旨在调查小鼠创伤性脑损伤 (TBI) 后胆固醇稳态如何改变，以及胆固醇的这种变化是否是该模型中报道的 Abeta 产量增加的原因。由于中枢神经系统胆固醇独立于外周胆固醇的波动，因此很难独立于外周胆固醇的影响来检查中枢神经系统中胆固醇的影响。使用 TBI 作为脑内胆固醇稳态功能失调的模型是一种新方法，用于研究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 后的事件进程，并且确定的途径可能有助于指导未来的药物开发研究。因此，该项目具有多学科优势，与中枢神经系统胆固醇、阿尔茨海默病和脑损伤领域相关。