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）：