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.

血管疾病可引起多发性梗塞性痴呆。然而，此外，血管疾病及其相关危险因素（例如高胆固醇血症）也可能加速阿尔茨海默病（AD）的进展。该项目的长期目标是使用现已广泛用于动脉粥样硬化研究的高胆固醇血症小鼠，确定系统性高胆固醇血症及其相关血管疾病对与 AD 发病机制相关的一系列参数的影响。具体来说，我们将利用对低密度脂蛋白受体基因进行靶向破坏的小鼠（LDLR -/- 小鼠）。通过调制 饮食中的胆固醇含量、这些小鼠的血浆胆固醇差异很大，并且相关血管疾病的程度可重复地从轻微到严重变化。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。我们将在两种神经可塑性和修复模型中研究高胆固醇血症对这些动物的功能后果，即内嗅皮层损伤后的修复和对成年海马神经发生的影响。通过行为测试将获得进一步的功能相关性，并且由于对全身性高胆固醇血症对脑胆固醇代谢的影响知之甚少，我们将检查一系列参数 胆固醇代谢，包括大脑中 24S-羟基胆固醇的产生。为了区分高胆固醇血症及其血管后果，当存在高胆固醇血症但很少有血管疾病时，将在短期饮食操作后对动物进行检查；当存在明显的血管疾病时，将在较长的治疗间隔后对动物进行检查。在每种情况下，都会对全身和脑微血管的变化进行定量评估。通过将 Tg2576 转基因培育到 LDLR -/- 背景上，确定全身性高胆固醇血症和血管疾病是否影响 AD 的 Tg2576 小鼠模型中的 Ab 产生、斑块负载和 tau 磷酸化，从而延长 LDLR -/- 小鼠的效果。最后，我们将通过 ELISA 检查患者样本中的 Ab 水平和 tau 构象变化，这些样本已进行脑血管病理学和淀粉样蛋白病理学评分。统称为这些 研究使我们有机会研究高胆固醇血症和血管疾病对小鼠和人类材料中一系列 AD 相关变化的影响。