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: 8974327
• 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/8974327
• 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; Health; 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; Process; Protein Isoforms; Proteins; Research; Rest; Severities; Symptoms; Tauopathies; Testing; Time; Transgenic Mice; Traumatic Brain Injury; Uncertainty; Work; adverse outcome; base; brain tissue; cerebral amyloidosis; clinically significant; cognitive function; design; effective therapy; genetic makeup; human subject; improved; in vivo; meetings; mouse model; neurofibrillary tangle formation; neurotoxic; prevent; protein misfolding; research study; 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两种主要类型的异常有关，“斑块”和“神经元缠结”。“我们的实验室，像大多数试图开发阿尔茨海默病新疗法的实验室一样，到目前为止一直专注于斑块。基于一些最近完成的研究，我们建议将我们的重点转移到神经元缠结。基于大脑铜水平影响神经元缠结发展的初步证据，该假设特别关注铜和缠结之间的关系。 目标：1）我们将确定铜是否可以直接作用于缠结的前体，即一种名为“tau”的大脑蛋白质。“2）我们将确定个人的铜基线水平是否影响 他们对治疗的反应能力，3）我们将确定铜是否对类型的影响 与散发性阿尔茨海默病相关的tau蛋白或与某些形式的遗传性额颞叶痴呆相关的tau蛋白类型。4)我们将确定防止蛋白质错误折叠的治疗是否可用于增强铜调节治疗的效果。 实验将在基因工程小鼠中进行，以表达阿尔茨海默病病理学的各个方面。小鼠将接受提高或降低脑铜水平的治疗，并测量对缠结病理学和记忆功能的影响。 方法：小鼠行为标准化测试，疾病相关蛋白的脑浓度，认知功能测试. 迄今为止的发现：铜似乎增加了tau蛋白磷酸化，并使神经元缠结小鼠的记忆力恶化。 临床相关性：这些实验的目的是导致临床试验的铜降低治疗阿尔茨海默氏症和相关痴呆症。 与退伍军人事务部任务的相关性：开发安全、有效的阿尔茨海默病和额颞叶痴呆症治疗方法属于退伍军人事务部的使命。由于创伤性脑损伤（TBI）中也可见神经纤维缠结，因此这项工作可能与VA使命有额外的相关性。