Targeting tau pathology with copper-modulating strategies in Alzheimers disease

通过铜调节策略针对阿尔茨海默病的 tau 病理学

• 批准号: 9339519
• 负责人: JOSEPH F QUINN
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339519
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Attenuated; Behavior; Brain; Cerebrum; Characteristics; Chemicals; Clinical; Clinical Research; Clinical Trials; Communities; Copper; Dementia; Development; Dietary Copper; Disease; Frontotemporal Dementia; Funding; Gender; Genes; Genetic Engineering; Genetically Engineered Mouse; Goals; Human; Individual; Industry; Inherited; Intervention; Lead; Life; Light; Measures; Memory; Mission; Molecular Chaperones; Monoclonal Antibodies; Mus; Names; Nervous System Physiology; Neurofibrillary Tangles; Outcome; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phosphorylation; Protein Isoforms; Proteins; Research; Rest; Severities; Standardization; Symptoms; Tauopathies; Testing; Time; Transgenic Mice; Traumatic Brain Injury; Uncertainty; Work; adverse outcome; base; brain tissue; cerebral amyloidosis; clinically relevant; clinically significant; cognitive function; cognitive testing; design; dietary excess; effective therapy; experimental study; genetic makeup; human subject; improved; in vivo; mouse model; neurofibrillary tangle formation; neurotoxic; prevent; protein misfolding; public health relevance; tau Proteins; tau mutation; tau phosphorylation; tauroursodeoxycholic acid; therapeutic target

DESCRIPTION (provided by applicant): Alzheimer's disease is associated with two main types of abnormalities in the brain, "plaques" and "neurofibrillary tangles." Our lab, like most labs trying to develop new treatments for Alzheimer's disease, has focused on the plaques up to this point. Based on a number of recently completed studies, we are proposing to shift our focus to the neurofibrillary tangles. Based on preliminary evidence that brain levels of copper affect the development of neurofibrillary tangles, the hypothesis is specifically focused on the relationship between copper and tangles. OBJECTIVES: 1) We will determine if copper can act directly on the precursor of the tangle, a brain protein named "tau." 2) We will determine if the individuals baseline level of copper affects their ability to respond to the treatment, 3) we will determine if copper has an effect on the type of tau associated with sporadic Alzheimer's disease or the type of tau associated with some forms of hereditary frontotemporal dementia. 4) we will determine if a treatment which prevents protein misfolding can be used to enhance the effects of copper modulating therapy. PLAN: Experiments will be conducted in mice which are genetically engineered to express aspects of Alzheimer's pathology. Mice will be given treatments that raise or lower brain copper levels, and the effects on tangle pathology and memory function will be measured. METHODS: Standardized tests of mouse behavior, brain concentrations of disease- associated proteins, tests of cognitive function. FINDINGS TO DATE: Copper seems to increase tau phosphorylation and worsen memory in mice with neurofibrillary tangles. CLINICAL RELEVANCE: These experiments are designed to lead to clinical trials of copper-lowering treatment for Alzheimer's disease and related dementias. RELEVANCE TO THE VA'S MISSION: Development of safe, effective therapies for Alzheimer's disease and frontotemporal dementia is within the VA mission. Since neurofibrillary tangles are also seen in traumatic brain injury (TBI), this work may have additional relevance to the VA mission.

描述（由申请人提供）： 阿尔茨海默氏病与大脑中的两种主要异常类型有关，“斑块”和“神经原纤维缠结”。就像大多数试图为阿尔茨海默氏病开发新疗法的实验室一样，我们的实验室一直集中在这一点上。基于许多最近完成的研究，我们建议将重点转移到神经纤维缠结上。基于铜的大脑水平影响神经纤维缠结的发展的初步证据，该假设专门针对铜与缠结之间的关系。 目的：1）我们将确定铜是否可以直接作用于缠结的前体，缠结的前体是一种名为“ tau”的脑蛋白。 2）我们将确定铜的基线水平是否影响 他们对治疗的反应能力，3）我们将确定铜是否对这种类型有影响 tau与零星的阿尔茨海默氏病或​​与某些形式的遗传性额颞痴呆相关的Tau类型。 4）我们将确定可以使用防止蛋白质错误折叠的治疗方法来增强铜调节疗法的影响。 计划：实验将在基因设计的小鼠中进行，以表达阿尔茨海默氏病的方面。将为小鼠提供升高或降低脑铜水平的治疗，并将测量对纠缠病理和记忆功能的影响。 方法：小鼠行为的标准化测试，疾病相关蛋白的大脑浓度，认知功能的测试。 迄今为止的发现：铜似乎会增加tau磷酸化，并在神经纤维缠结的小鼠中恶化记忆。 临床相关性：这些实验旨在导致对阿尔茨海默氏病和相关痴呆症的降铜治疗进行临床试验。 与VA的使命相关：开发针对阿尔茨海默氏病和额颞痴呆的安全有效疗法是VA的任务。由于在创伤性脑损伤（TBI）中还可以看到神经纤维缠结，因此这项工作可能与VA任务具有更多相关性。