Cholesterol and brain injury-induced Abeta

摘要人类脑外伤可能是发生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死后的大脑中存在A- β斑块。a -是一种神经毒性肽，它会形成斑块，而斑块是阿尔茨海默病的主要病因。a - β的产生和积累可能是脑外伤后数小时或数天内发生的神经元细胞损失的原因。然而，为什么a - β的产生在脑外伤后增加尚不清楚。通过使用脑外伤动物模型，我们可以阐明与a - β产生有关的机制，并了解脑外伤后神经元细胞死亡的途径。a - β是在跨膜前体蛋白被切割时形成的。胆固醇是一种完整的膜脂，在大脑中含量很高。在体外，当细胞胆固醇水平升高时，a - β前体蛋白的裂解也会增加。胆固醇水平的降低会导致A- β形成的减少。这些结果已经被体内降胆固醇药物复制。在人类中，服用降胆固醇药物可能会减少阿尔茨海默病的发病率。啮齿动物的创伤性脑外伤会导致一系列细胞死亡，从直接撞击的区域开始。随着细胞的死亡和降解，它们的组成部分被循环利用。我们假设，这导致损伤区域周围细胞中的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。我们的目标是通过以下方法来验证这一假设：1)测量啮齿动物脑外伤后胆固醇相关调节蛋白和a - β反应；2)在损伤前后尝试通过使用LXR激动剂（to -901317）和他汀类药物（洛伐他汀）干预和抑制这些变化。我们认为TO-901317会阻止受损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后的认知恢复和损伤大小有益，因此我们将研究洛伐他汀对TBI后胆固醇反应的影响，以及它的抗炎作用，试图阐明其可能的作用机制。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）后胆固醇稳态是如何改变的，以及这种胆固醇的变化是否导致了该模型中报道的β的产生增加。由于中枢神经系统胆固醇与外周胆固醇的波动无关，因此很难独立于外周检查胆固醇对中枢神经系统的影响。使用脑外伤作为功能失调的脑内胆固醇稳态模型是一种新的方法来研究中枢神经系统胆固醇变化如何单独改变β水平。此外，我们在本项目中提供的数据将有助于确定TBI后的事件过程，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。

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.