Cholesterol and brain injury-induced Abeta

胆固醇和脑损伤引起的 Abeta

基本信息

  • 批准号:
    7314586
  • 负责人:
  • 金额:
    $ 7.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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(申请人提供):人类中的抽象脑创伤可能是发展阿尔茨海默氏病的重要危险因素。许多研究表明,在单一生产力脑创伤受害者的后大脑中存在A-Beta斑块。 A-beta是神经毒性肽,形成斑块,这是阿尔茨海默氏病的主要病理。 A-beta的产生和积累可能是导致脑创伤后数小时和几天发生的神经元细胞损失。但是,为什么尚不清楚脑创伤后A-beta的产生增加。通过使用脑部创伤的动物模型,我们可以阐明与A-beta产生有关的机制,并了解脑创伤后涉及神经元细胞死亡的途径。裂解跨膜前体蛋白时会形成A-Beta。胆固醇是一种整体膜脂质,在大脑中以高浓度发现。在体外,当细胞胆固醇水平升高时,前体蛋白向A-beta的切割也会增加。胆固醇水平的降低会导致A-beta形成的降低。这些结果已通过体内降低胆固醇的药物复制。在人类中,服用降低胆固醇的药物可能会降低阿尔茨海默氏病的发生率。啮齿动物中的创伤性脑外伤会导致一系列细胞死亡,从直接撞击区域开始。当细胞死亡并降解时,它们的组成部分被回收。我们假设这导致立即周围受伤区域的细胞中胆固醇水平的短暂增加,并且这种增加是脑创伤后A-beta水平的急性增加。我们的目的是通过1)测量啮齿动物的脑创伤后测量与胆固醇相关的调节蛋白和A-beta反应,以及2)试图通过使用LXR激动剂(TO-901317)和sttectin(to-901317)和statinin(lovastatin)进行干预和抑制这些变化。我们认为,TO-901317将防止受伤区域周围的细胞接受受损神经元的胆固醇,这将防止TBI诱导的A-Beta尖峰。先前已证明他汀类药物对TBI后的认知恢复和病变大小是有益的,因此我们将研究洛伐他汀对TBI胆固醇反应的影响及其抗炎作用,以阐明可能的作用机制。这些研究旨在了解如何产生A-Beta,以及为什么脑损伤会导致神经毒素的产生,A-BETA项目的相关性本研究旨在研究小鼠创伤性脑损伤(TBI)后如何改变胆固醇的稳态,以及胆固醇中胆固醇的这种变化是否负责这种模型中的Abeta产量增加。由于CNS胆固醇与外周胆固醇的波动无关,因此很难检查胆固醇在中枢神经系统中与周围作用无关的作用。使用TBI作为功能失调的脑胆固醇稳态的模型是一种新的方法,可以研究单独使用中枢神经系统胆固醇的变化如何改变ABETA水平。此外,我们在该项目中提供的数据将有助于确定TBI之后的事件过程,并且所识别的途径可以帮助指导未来的药物开发研究。因此,该项目具有多学科的好处,并且与CNS胆固醇,阿尔茨海默氏病和脑损伤的领域有关。

项目成果

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MARK P BURNS其他文献

MARK P BURNS的其他文献

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{{ truncateString('MARK P BURNS', 18)}}的其他基金

Recovering amnestic memories from the repeat head impact brain
从重复头部撞击大脑中恢复失忆记忆
  • 批准号:
    10184658
  • 财政年份:
    2021
  • 资助金额:
    $ 7.76万
  • 项目类别:
Detecting the disruption and recovery of synaptic connectivity after TBI
检测 TBI 后突触连接的破坏和恢复
  • 批准号:
    10092458
  • 财政年份:
    2018
  • 资助金额:
    $ 7.76万
  • 项目类别:
Tau-independent effects of high frequency head impact on cognition and neurobehavior
高频头部影响认知和神经行为的 Tau 独立效应
  • 批准号:
    10200916
  • 财政年份:
    2018
  • 资助金额:
    $ 7.76万
  • 项目类别:
Detecting the disruption and recovery of synaptic connectivity after TBI
检测 TBI 后突触连接的破坏和恢复
  • 批准号:
    10261488
  • 财政年份:
    2018
  • 资助金额:
    $ 7.76万
  • 项目类别:
Tau-independent effects of high frequency head impact on cognition and neurobehavior
高频头部影响认知和神经行为的 Tau 独立效应
  • 批准号:
    10447059
  • 财政年份:
    2018
  • 资助金额:
    $ 7.76万
  • 项目类别:
The role of apoE and APOE genotype in amyloid-beta clearance after TBI
apoE 和 APOE 基因型在 TBI 后β-淀粉样蛋白清除中的作用
  • 批准号:
    8729697
  • 财政年份:
    2013
  • 资助金额:
    $ 7.76万
  • 项目类别:
The role of apoE and APOE genotype in amyloid-beta clearance after TBI
apoE 和 APOE 基因型在 TBI 后β-淀粉样蛋白清除中的作用
  • 批准号:
    8608016
  • 财政年份:
    2013
  • 资助金额:
    $ 7.76万
  • 项目类别:
The role of apoE and APOE genotype in amyloid-beta clearance after TBI
apoE 和 APOE 基因型在 TBI 后β-淀粉样蛋白清除中的作用
  • 批准号:
    8528057
  • 财政年份:
    2013
  • 资助金额:
    $ 7.76万
  • 项目类别:
The role of Abeta in injury-induced cell death
Abeta 在损伤诱导的细胞死亡中的作用
  • 批准号:
    8044951
  • 财政年份:
    2010
  • 资助金额:
    $ 7.76万
  • 项目类别:
The role of Abeta in injury-induced cell death
Abeta 在损伤诱导的细胞死亡中的作用
  • 批准号:
    8126336
  • 财政年份:
    2010
  • 资助金额:
    $ 7.76万
  • 项目类别:

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脊髓损伤后神经炎症的昼夜节律控制
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