Understanding the role of TDP-43 in Alzheimers disease and FTLD

了解 TDP-43 在阿尔茨海默病和 FTLD 中的作用

• 批准号: 7945774
• 负责人: Keith A Josephs
• 金额: $ 33.6万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7945774
• 关键词: Affect; Alzheimer' s Disease; American; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Appearance; Arts; Atlases; Atrophic; Autopsy; Brain; Brain scan; Characteristics; Clinic; Clinical; Corticospinal Tracts; DNA-Binding Proteins; Data; Dementia; Deposition; Development; Disease; Elderly; Frequencies; Frontotemporal Lobar Degenerations; Funding; Goals; Health; Image; Imaging Techniques; Individual; Lobar; MRI Scans; Magnetic Resonance Imaging; Measures; Methods; Molecular; Motor Neurons; Movement Disorders; Neurodegenerative Disorders; Neurofibrillary Tangles; Parkinson Disease; Pathology; Patients; Pattern; Prevalence; Process; Progressive Supranuclear Palsy; Proteins; Radiology Specialty; Reporting; Research; Research Personnel; Role; Scientist; Senile Plaques; Specialist; Surface; Testing; United States National Institutes of Health; aging population; alpha synuclein; base; brain cell; clinically significant; cohort; hippocampal atrophy; immunoreactivity; improved; molecular pathology; morphometry; motor neuron degeneration; neuropsychological; public health relevance; response; tau Proteins; therapy development

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that cause dementia and hence are a major health concern. Both diseases affect the elderly and are increasing in prevalence as the aging population increases. These diseases are both associated with pathological changes in the brain including the deposition of abnormal proteins. Alzheimer's disease is associated with deposition of the proteins beta-amyloid and tau, whereas recently FTLD has been shown to be associated with the transactive response DNA binding protein 43 (TDP-43). We recently demonstrated that almost 50% of patients with AD also have deposition of the protein TDP-43 in their brain cells. This finding may be an important clue to understanding the underlying disease mechanisms causing FTLD and AD. However, it is currently unknown whether the role of TDP-43 in AD differs from its role in FTLD and whether TDP-43 deposition in AD has any clinical significance. The main objective of this R01 is to better understand the role, and hence significance, of TDP-43 in FTLD and AD. To accomplish this goal we will study a large cohort of autopsy confirmed cases of AD and FTLD that were ascertained through our NIH funded Alzheimer's Disease Research Center. We will assess and compare pathological characteristics of TDP-43 in FTLD and AD including its distribution, intracellular appearance, association with tau, and protein fragmentation. Associations between pathological characteristics and clinical and imaging characteristics will then be determined. Imaging-pathological associations will be investigated using state of the art automated imaging techniques, including voxel-based morphometry and atlas-based parcellation. The methods will be performed by a team of world renowned scientists including a dementia and movement disorder specialist, a neuropathologist, radiology researchers, and biostatisticians. The long term goal of our research is to aid in the development of treatments for AD and FTLD that will likely target underlying proteins. PUBLIC HEALTH RELEVANCE: This study will improve our understanding of the role of the transactive DNA binding protein 43 (TDP-43) in Alzheimer's disease and frontototemporal lobar degeneration. A better understanding of the role of TDP-43 is important to the development of targeted treatments for both diseases. Alzheimer's disease and frontototemporal lobar degeneration affect over 5 million Americans.

描述（由申请人提供）：阿尔茨海默氏病（AD）和额颞叶变性（FTLD）是神经退行性疾病，引起痴呆，因此是主要的健康问题。这两种疾病都会影响老年人，并且随着人口衰老的增加，患病率正在增加。这些疾病都与大脑的病理变化有关，包括异常蛋白质的沉积。阿尔茨海默氏病与蛋白质β-淀粉样蛋白和tau的沉积有关，而最近的FTLD与交易反应DNA结合蛋白43（TDP-43）有关。我们最近证明，几乎50％的AD患者在其脑细胞中还具有蛋白质TDP-43的沉积。这一发现可能是理解导致FTLD和AD的潜在疾病机制的重要线索。但是，目前尚不清楚TDP-43在AD中的作用与其在FTLD中的作用以及TDP-43 AD中的沉积是否具有任何临床意义。该R01的主要目的是更好地了解FTLD和AD中TDP-43的作用，因此是显着性。为了实现这一目标，我们将研究大量尸检确认的AD和FTLD病例，这些病例已通过我们的NIH资助的阿尔茨海默氏病研究中心确定。我们将评估和比较TDP-43在FTLD和AD中的病理特征，包括其分布，细胞内外观，与TAU的关联和蛋白质碎片。然后将确定病理特征与临床和成像特征之间的关联。成像病理学关联将使用最先进的自动成像技术（包括基于体素的形态计量学和基于ATLAS的分析）进行研究。这些方法将由世界著名科学家团队进行，包括痴呆症和运动障碍专家，神经病理学家，放射学研究人员和生物统计学家。我们研究的长期目标是帮助开发可能针对潜在蛋白质的AD和FTLD治疗。 公共卫生相关性：这项研究将提高我们对交易DNA结合蛋白43（TDP-43）在阿尔茨海默氏病和额颞Lobar变性中的作用的理解。更好地了解TDP-43的作用对于两种疾病的有针对性治疗的发展很重要。阿尔茨海默氏病和额颞叶变性影响了超过500万美国人。