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: 8634332
• 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/8634332
• 关键词: A Mouse; Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloidosis; 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; Genetic Engineering; Genetically Engineered Mouse; Goals; Human; Individual; Industry; Inherited; Intervention; Lead; Life; Light; Measures; Memory; Mission; Modeling; 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; clinically relevant; clinically significant; cognitive function; design; effective therapy; human subject; improved; in vivo; meetings; mouse model; neurofibrillary tangle formation; neurotoxic; prevent; protein misfolding; public health relevance; research study; tau Proteins; tau mutation; tau phosphorylation; tauroursodeoxycholic acid; therapeutic target

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.

阿尔茨海默病与大脑的两种主要异常有关， “斑块”和“神经原纤维缠结”。我们的实验室，就像大多数试图开发的实验室一样 迄今为止，阿尔茨海默病的新疗法主要集中在斑块上。 根据最近完成的一些研究，我们建议改变我们的 重点关注神经原纤维缠结。基于大脑水平的初步证据 铜影响神经原纤维缠结的发展，假设是 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 tangle，一种名为“tau”的大脑蛋白质。 2) 我们将确定个人的基线是否 铜的水平影响他们对治疗的反应能力，3）我们将确定 铜是否对与散发性阿尔茨海默病相关的 tau 蛋白类型有影响 与某些形式的遗传性额颞叶相关的疾病或 tau 蛋白类型 失智。 4) 我们将确定是否有一种治疗方法可以防止蛋白质错误折叠 可用于增强铜调节疗法的效果。 计划：实验将在经过基因改造的小鼠中进行 表达阿尔茨海默病病理学的各个方面。将对小鼠进行治疗，以提高 或降低脑铜水平，以及对缠结病理和记忆的影响 将测量功能。 方法：对小鼠行为、大脑疾病浓度进行标准化测试 相关蛋白质，认知功能测试。 迄今为止的发现：铜似乎会增加 tau 磷酸化并使其恶化 患有神经原纤维缠结的小鼠的记忆。 临床相关性：这些实验旨在进行以下临床试验： 用于治疗阿尔茨海默病和相关痴呆症的低铜治疗。 与 VA 使命的相关性：开发安全、有效的治疗方法 阿尔茨海默病和额颞叶痴呆属于退伍军人事务部的任务范围。自从 神经原纤维缠结也见于创伤性脑损伤 (TBI)，这项工作可能 与 VA 使命有额外的相关性。