Neuroinflammation in Cholesterol-Induced AD Pathogenesis

胆固醇诱导的 AD 发病机制中的神经炎症

基本信息

批准号：
7591029
负责人：
NARAYAN R BHAT
金额：
$ 28.71万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-25 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7591029
关键词：
Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Precursor Amyloid deposition Anti-Inflammatory Agents Anti-inflammatory Antibiotics Apolipoprotein E Astrocytes Attenuated Behavioral Biochemical Brain Brain region Cell Culture Techniques Cells Cessation of life Characteristics Cholesterol Cholesterol Homeostasis Clinical Research Coculture Techniques Dementia Detection Diet Dietary Practices Dietary intake Disease Elderly Endothelial Cells Environment Enzymes Epidemiology Experimental Genetics Failure Fatty acid glycerol esters Functional disorder Generations Genes Genetic Genetic Polymorphism Hippocampal Formation Human Incidence Individual Inflammation Mediators Inflammatory Response Injury Interleukin-6 Interleukins Knock-out LDL Cholesterol Lipoproteins Ligands Link Lipoproteins Liver Low Density Lipoprotein Receptor Mediating Mediator of activation protein Metabolism Microglia Minocycline Modeling Mouse Strains Mus Nature Nerve Degeneration Neurofibrillary Tangles Neuroglia Neuronal Injury Neurons Nuclear Receptors Outcome Study Participant Pathogenesis Pathology Peptides Performance Pharmaceutical Preparations Play Presynaptic Terminals Process Production Property Prosencephalon Protein Isoforms Proteins Reactive Oxygen Species Receptor Gene Research Personnel Retrospective Studies Role Stimulus Synapses Synaptophysin Techniques Testing Tetracyclines Therapeutic Therapeutic Uses Transgenic Mice Tumor Necrosis Factor-alpha Tumor Necrosis Factors Upper arm Water abeta accumulation amyloid pathology amyloid precursor protein processing basal forebrain cell type cerebrovascular cytokine extracellular feeding hypercholesterolemia immunoreactivity improved neuroinflammation neuroprotection neurotoxic novel outcome forecast oxidation programs receptor response theories

项目摘要

Alzheimer's disease (AD), a progressive neurodegenerative condition, is the most prevalent form of dementia in the elderly. The pathology is characterized by an accumulation of amyloid beta (Ap), the product of amyloid precursor protein (APR). The amyloid cascade hypothesis proposes that Ap oligomers cause neuronal injury both directly and indirectly via an activation of microglia and their production of neurotoxic molecules. Recent findings (genetic, experimental, and epidemiological) suggest a link between abnormal cholesterol metabolism and the pathogenesis of AD. The project tests the hypothesis that failure of cholesterol homeostasis facilitates an exacerbated neuroinflammatory response in association with increased Ap generation that, in turn, leads to neurodegeneration characteristic of AD. The studies willuse: high fat/cholesterol diet fed hypercholesterolemic, low density lipoprotein receptor knockout (LDLR-/-) mice, a mouse strain expressing the wild type human APR (akin to sporadic AD), as well as the cross between the two. The specific objectives of the project are as follows: * Determine neuroinflammatory changes in brain regions of high cholesterol-fed LDLR-/-, wtAPP and wtAPP/LDLR-/- mice by immunohistochemical detection of activated microglia and cerebrovascular cells in relation to amyloid levels and synaptotoxicity (i.e., loss of synaptophysin-immunoreactivity). Inflammatory mediators (i.e., cytokines, pro-oxidant enzymes), Ap peptides, and proteins involved in cholesterol homeostasis (i.e., ApoE, ABCA1) will be quantified by biochemical and immunochemical techniques. 4 Determine the nature and role of pro- and anti-inflammatory stimuli relevant to impaired brain chol- esterol metabolism using cell culture models. Cultures of glia and glial-neuronal co-cultures will be used to investigate the effects of oxidized lipoproteins and ApoE isoforms (in the presence or absence of Ap) on glial inflammatory response (i.e., production of mediators) and on neuronal APR processing. Also, the anti- inflammatory and anti-amyloidogenic effects of oxysterol ligands of a nuclear receptor, i.e., Liver X Receptor (LXR) will be examined and the mechanisms explored. *Test the therapeutic potential of a synthetic LXR ligand (T0901317) with both cholesterol lowering and anti-inflammatory properties, and minocycline, a tetracycline derivative known to suppress microglial activa- tion, by examining neuropathological (i.e., Ap peptide levels and synaptotoxicity) and behavioral changes (8- arm water maze performance) in parallel to attenuated neuroinflammation in hypercholesterolemic mice. The outcome of these studies should have implications for developing novel and effective anti- inflammatory treatments for AD.

阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，是最普遍的形式老年人的痴呆症。病理的特征是淀粉样β（AP）的积累淀粉样蛋白（APR）的淀粉样前体蛋白。淀粉样蛋白级联假设提出了AP低聚物引起的通过小胶质细胞的激活直接和间接地神经元损伤及其神经毒性的产生分子。最新发现（遗传，实验和流行病学）表明异常之间有联系胆固醇代谢和AD的发病机理。该项目检验了以下假设胆固醇稳态有助于与之相关的神经炎症反应增加了AP的产生，从而导致AD的神经变性特征。研究将进行：高脂肪/胆固醇饮食喂养高胆固醇，低密度脂蛋白受体敲除（LDLR - / - ）小鼠，表达野生型人类APR（类似于零星AD）的小鼠菌株，以及二。该项目的具体目标如下： *确定高胆固醇喂养的LDLR的大脑区域的神经炎症变化 - / - ，WTAPP和 WTAPP/LDLR - / - 小鼠通过免疫组织化学检测活化的小胶质细胞和脑血管细胞的免疫组织化学检测与淀粉样蛋白水平和突触毒性的关系（即突触素 - 免疫反应性的丧失）。炎症介质（即细胞因子，促氧化酶），AP肽和参与胆固醇的蛋白稳态（即APOE，ABCA1）将通过生化和免疫化学技术来量化。 4确定与脑chol受损相关的促和抗炎刺激的性质和作用酯代谢使用细胞培养模型。神经胶质和神经神经元共培养的培养物将用于研究氧化的脂蛋白和APOE同工型（在存在AP存在或不存在AP）对神经胶质的影响炎症反应（即介体的产生）和神经元的APR处理。另外，抗核受体的氧蛋白酶配体的炎症和抗淀粉样生成作用，即肝X受体（LXR）将进行检查，并探讨了机制。 *与降低胆固醇和抗炎特性和米诺环素，一种四环素衍生物，已知可抑制小胶质细胞活性通过检查神经病理学（即AP肽水平和突触毒素）和行为变化（8-- 手臂水迷宫性能）与高胆固醇小鼠的神经炎症平行。这些研究的结果应该对发展新颖有效的抗 AD的炎症治疗。