HYPERCHOLESTEROLEMIA AND AD NEUROBIOLOGY

高胆固醇血症和 AD 神经生物学

• 批准号: 6808102
• 负责人: Joseph D. Buxbaum
• 金额: $ 27.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6808102
• 关键词: Alzheimer' s disease; amyloid proteins; atherosclerosis; cardiovascular disorder; cholesterol; disease /disorder etiology; disease /disorder model; disease /disorder proneness /risk; gene expression; genetically modified animals; human tissue; hypercholesterolemia; laboratory mouse; lipid metabolism; low density lipoprotein; neural plasticity; neuroanatomy; neurobiology; neurogenesis; neurogenetics; neuropathology; neuropsychological tests; tau proteins

Vascular disease can cause multi-infarct dementia. However in addition vascular disease and its associated risk factors such as hypercholesterolemia may also hasten the progression of Alzheimer's disease (AD). The long-range goal of this project is to determine the effect that systemic hypercholesterolemia and its associated vascular disease have on series of parameters of relevance to AD pathogenesis using hypercholesterolemic mice that are now widely used in atherosclerosis research. Specifically, we will utilize mice with a targeted disruption of the low-density lipoprotein receptor gene (LDLR -/- mice). By modulating the amount of cholesterol in the diet, plasma cholesterol in these mice can be widely varied and the degree of associated vascular disease reproducibly varied from minimal to severe. As biochemical markers of the AD process we will examine Abeta (Ab) production and tau phosphorylation. We will examine the functional consequences of hypercholesterolemia in these animals in two models of neural plasticity and repair, namely repair after entorhinal cortex lesioning and effect on neurogenesis in the adult hippocampus. A further functional correlate will be obtained through behavioral testing and since little is known about the effects of systemic hypercholesterolemia on brain cholesterol metabolism we will examine a series of parameters of cholesterol metabolism including 24S-hydroxycholesterol production in brain. To distinguish the effects hypercholesterolemia from its vascular consequences animals will be examined after short-term dietary manipulations when hypercholesterolemia is present but little vascular disease and after longer treatment intervals when significant vascular disease will be present. In each case both systemic and cerebral microvascular changes will be quantitatively assessed. Effects in LDLR -/- mice will be extended by determining if systemic hypercholesterolemia and vascular disease influence Ab production, plaque load and tau phosphorylation in the Tg2576 mouse model of AD by breeding the Tg2576 transgene onto an LDLR -/-background. Finally, we will examine Ab levels and tau conformational changes by ELISA in patient samples that have been scored for cerebrovascular pathology and amyloid pathology. Collectively these studies give us the opportunity to examine the effects of hypercholesterolemia and vascular disease on a series of AD related changes in both mouse and human material.

血管疾病会引起多侵袭性痴呆。但是，此外，血管疾病及其相关的危险因素（例如高胆固醇血症）也可能会加快阿尔茨海默氏病（AD）的进展。该项目的远距离目标是确定系统性高胆固醇血症及其相关的血管疾病对使用高胆固醇血症小鼠的一系列与AD发病机理相关的参数，该参数现在已在动脉粥样硬化研究中广泛使用。具体而言，我们将利用低密度脂蛋白受体基因（LDLR - / - 小鼠）靶向破坏的小鼠。通过调节 饮食中胆固醇的含量，这些小鼠中的血浆胆固醇的含量可以广泛变化，并且相关的血管疾病的程度可重复地从最小到重度变化。作为AD过程的生化标志物，我们将检查Abeta（AB）的产生和Tau磷酸化。我们将检查两种神经可塑性和修复模型中高胆固醇血症的功能后果，即肠系膜皮层病变后修复以及对成年海马的神经发生的影响。将通过行为测试获得进一步的功能相关性，并且由于全身性高胆固醇血症对脑胆固醇代谢的影响知之甚少，所以我们将研究一系列参数 胆固醇代谢包括大脑中的24秒羟基胆固醇。为了区分高胆固醇血症的影响，高胆固醇血症在短期饮食操纵后，将在高胆固醇血症（但几乎没有血管疾病）中检查动物，并且在存在明显的血管疾病时更长的治疗间隔后进行检查。在每种情况下，全身性和脑微血管变化均应定量评估。通过确定全身性高胆固醇血症和血管疾病是否影响AB的产生，斑块负荷和TAU磷酸化，通过将TG2576 AD的TG2576 Transgene育种TG2576小鼠模型来扩展LDLR - / - 小鼠的影响。最后，我们将检查ELISA的AB水平和TAU构象变化，这些患者样本中的脑血管病理学和淀粉样病理学评分。集体这些 研究使我们有机会检查高胆固醇血症和血管疾病对小鼠和人类物质相关的一系列相关变化的影响。