OXIDATIVE DAMAGE TO SYNAPTIC COMPARTMENTS IN AD

AD 突触区室的氧化损伤

基本信息

批准号：
7393172
负责人：
GREGORY M COLE
金额：
$ 23.71万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7393172
关键词：
3-nitrotyrosine Abeta synthesis Actin-Binding Protein Actins Address Adult Aging Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloidosis Animal Model Animals Antioxidants Apoptotic Ascorbic Acid Biochemical Biochemical Pathway Body Weight Brain Caspase Caspase Inhibitor Chromosome Pairing Chronic Cleaved cell Clinic Clinical Clinical Trials Cognition Cognitive Cognitive deficits Collaborations Curcumin Cytochromes DLG4 gene DNA Data Defect Dementia Dendritic Spines Deterioration Development Diet Docosahexaenoic Acids Doctor of Medicine Doctor of Philosophy Dose Education End Point Environmental Risk Factor Enzymes Epidemiologic Studies Evaluation Fatty Acids Fatty acid glycerol esters Feedback Flow Cytometry Functional disorder Generations Genetic Human Hydroxyl Radical ITGAM gene ITGAX gene Impaired cognition In Vitro Individual Inflammation Infusion procedures Intervention Intestines Investigation Isoprostanes Label Lead Link Lipid Peroxidation Lipids Lipoproteins Localized Measurement Measures Mediating Memory Mental Retardation Methods Microglia Mission Mitochondria Modeling Molecular Genetics Mus Neurons Numbers Omega-3 Fatty Acids Pathogenesis Pathologic Pathology Pathway interactions Patients Peroxonitrite Phagocytosis Pharmaceutical Preparations Phase Plasma Play Preparation Principal Investigator Production Proteins RNA Reactive Oxygen Species Regulation Relative (related person)Reporting Research Rodent Role Safflower Oil Sampling Site Source Spices Standards of Weights and Measures Superoxides Synapses Synaptic plasticity Synaptophysin Synaptosomes Syndrome Testing Tg2576 Therapeutic Therapeutic Agents Tissues Tocopherols Toxic effect Transgenes Transgenic Animals Transgenic Mice Transgenic Model Transgenic Organisms Treatment Efficacy Treatment Protocols Tumeric Up-Regulation Vertebral column Vitamin E Western Blotting Work abeta accumulation age related aged antioxidant therapy base brain tissue clinically relevant cofilin day dietary antioxidant disorder control immunoreactivity in vivo indexing mouse model neuropathology novel novel therapeutics oxidation postsynaptic presynaptic presynaptic density protein 95 programs research study response secretase synaptic function tetrahydrocurcumin

项目摘要

Synaptic dysfunction and loss appears central to clinical deficits in Alzheimer's disease (AD), but the causes of synapse loss and methods of intervention are poorly understood. Oxidative damage to proteins, DNA, RNA and lipids is increased in AD brain, including large increases in oxidized docosahexaenoic acid (DHA), an essential omega-3 fatty acid required for synaptic function. Our preliminary data show that a diet deficient in DHA results in CNS depletion of DHA, increased oxidative damage, caspase activation, Abeta accumulation and dramatic postsynaptic marker loss selectively in aging APPsw transgenic animals. DHA and synaptic marker losses in transgene positive animals correlate with increased oxidative damage. Our central hypothesis is that focal synaptic oxidative damage due to local Abeta42 accumulation drives a positive feedback loop resulting in increased Abeta production, oxidative damage, synaptic dysfunction and selective postsynaptic marker loss. Relevance to AD is supported by increased oxidized DHA, selective postsynaptic marker loss and flow cytometric evaluations showing increased synaptosomal apoptotic mitochondrial marker and Abeta labeling in AD vs. controls. Available results argue that supplemental Vit E, currently the standard treatment for oxidative damage in AD, may offer only limited protection against peroxynitrite, DHA oxidation, synaptic damage and clinical progression. In contrast, our animal model data show the phenolic antioxidant, curcumin, affords strong protection against multiple putative amyloid cascade endpoints including oxidative damage, inflammation (IL-1beta, TNF-a, CD11b, iNOS), amyloid accumulation, postsynaptic marker loss and cognitive deficits. By measuring the treatment's impact on CNS pathologic markers in animal models, we expect to validate accessible, but indirect or "surrogate" measures in humans that will be useful in assessing efficacy in clinical trials. We will test our central hypothesis using animal models to define optimum antioxidant treatments that ameliorate amyloidosis, oxidative damage and synaptic pathology in AD and confirm clinical relevance of the implicated biochemical pathways using AD tissue from the Neuropathology and Molecular Genetics Core.

突触功能障碍和缺失似乎是阿尔茨海默病 (AD) 临床缺陷的核心，但人们对突触缺失的原因和干预方法知之甚少。 AD 大脑中蛋白质、DNA、RNA 和脂质的氧化损伤增加，包括氧化二十二碳六烯酸 (DHA) 的大量增加，DHA 是突触功能所需的必需 omega-3 脂肪酸。我们的初步数据表明，在衰老的 APPsw 转基因动物中，缺乏 DHA 的饮食会导致中枢神经系统 DHA 消耗、氧化损伤增加、半胱天冬酶激活、Abeta 积累和突触后标记物选择性显着丧失。转基因阳性动物的 DHA 和突触标记物损失与氧化损伤的增加相关。我们的中心假设是，局部 Abeta42 积累导致的局灶性突触氧化损伤驱动正反馈回路，导致 Abeta 产生增加、氧化损伤、突触功能障碍和选择性突触后标记物丢失。氧化 DHA 增加、选择性突触后标记物丢失以及流式细胞术评估显示 AD 与对照组相比，突触体凋亡线粒体标记物和 Abeta 标记增加，支持了与 AD 的相关性。现有结果表明，补充维生素 E（目前 AD 氧化损伤的标准治疗方法）可能只能提供有限的针对过氧亚硝酸盐、DHA 氧化、突触损伤的保护作用和临床进展。相比之下，我们的动物模型数据显示，酚类抗氧化剂姜黄素可针对多种假定的淀粉样蛋白级联终点提供强有力的保护，包括氧化损伤、炎症（IL-1β、TNF-a、CD11b、iNOS）、淀粉样蛋白积累、突触后标记物丢失和认知能力。赤字。通过在动物模型中测量治疗对中枢神经系统病理标志物的影响，我们期望在人类中验证可访问的、但间接或“替代”的措施，这将有助于评估临床试验的疗效。我们将使用动物模型测试我们的中心假设，以确定改善 AD 中淀粉样变性、氧化损伤和突触病理的最佳抗氧化治疗，并使用神经病理学和分子遗传学核心的 AD 组织确认所涉及的生化途径的临床相关性。