Cholesterol and brain injury-induced Abeta

描述(由申请人提供)：人类的脑创伤可能是发展为阿尔茨海默病的一个重要风险因素。多项研究表明，单发脑外伤患者死后大脑中存在A-β斑块。A-β是一种神经毒肽，它形成斑块，这是阿尔茨海默病的主要病理。A-β的产生和积累可能是脑损伤后数小时和数天内发生的神经细胞丢失的原因。然而，为什么脑创伤后A-β的产生增加尚不清楚。通过使用脑创伤的动物模型，我们可以阐明参与A-β产生的机制，以及了解脑创伤后神经细胞死亡的途径。当跨膜前体蛋白被切割时，就会形成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，前体蛋白裂解成A-β的能力也会增加。胆固醇水平的降低会导致A-β形成的减少。这些结果在体内的降胆固醇药物中也得到了复制。在人类中，服用降胆固醇药物可能会降低阿尔茨海默病的发病率。啮齿动物的创伤性脑损伤会导致一连串的细胞死亡，从直接影响的区域开始。当细胞死亡和降解时，它们的组成部分被回收。我们假设这会导致损伤区域周围细胞中胆固醇水平的一过性增加，这种增加是脑创伤后A-β水平急剧上升的原因。我们的目标是通过1)测量啮齿类动物脑创伤后胆固醇相关调节蛋白和A-β反应来验证这一假说，以及2)尝试在损伤前后使用低分子肝素受体激动剂(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，这将阻止脑损伤诱导的A-β峰值。他汀类药物此前已被证明对脑损伤后的认知恢复和病变大小有好处，因此我们将研究洛伐他汀对脑损伤后胆固醇反应的影响及其抗炎作用，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探讨小鼠创伤性脑损伤(TBI)后胆固醇稳态是如何改变的，以及这种胆固醇变化是否与该模型中已报道的Abeta产生增加有关。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研究中枢神经系统中胆固醇的影响。使用脑损伤作为脑内胆固醇稳态失调的模型是一种新的方法，可以研究仅中枢神经系统胆固醇的变化如何改变Abeta水平。此外，我们在这个项目中提供的数据将有助于确定脑外伤后的事件进程，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，涉及中枢神经系统胆固醇、阿尔茨海默病和脑损伤等领域。

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.