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: 8299525
• 负责人: Keith A Josephs
• 金额: $ 30.88万
• 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/8299525
• 关键词: Affect; Alzheimer' s Disease; American; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Appearance; 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; protein TDP-43; 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）：阿尔茨海默病（AD）和额颞叶变性（FTLD）是导致痴呆的神经退行性疾病，因此是主要的健康问题。这两种疾病都会影响老年人，并且随着人口老龄化的增加，患病率也在增加。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。阿尔茨海默病与 β-淀粉样蛋白和 tau 蛋白的沉积有关，而最近 FTLD 已被证明与反式反应 DNA 结合蛋白 43 (TDP-43) 相关。我们最近证明，几乎 50% 的 AD 患者的脑细胞中也有蛋白质 TDP-43 的沉积。这一发现可能是了解导致 FTLD 和 AD 的潜在疾病机制的重要线索。然而，目前尚不清楚TDP-43在AD中的作用是否不同于其在FTLD中的作用，以及TDP-43沉积在AD中是否具有任何临床意义。本 R01 的主要目标是更好地了解 TDP-43 在 FTLD 和 AD 中的作用及其重要性。为了实现这一目标，我们将研究大量尸检确诊的 AD 和 FTLD 病例，这些病例是通过我们 NIH 资助的阿尔茨海默病研究中心确定的。我们将评估和比较 FTLD 和 AD 中 TDP-43 的病理特征，包括其分布、细胞内外观、与 tau 的关联以及蛋白质碎片。然后将确定病理特征与临床和影像特征之间的关联。将使用最先进的自动成像技术来研究成像病理关联，包括基于体素的形态测量和基于图集的分割。这些方法将由世界知名的科学家团队执行，其中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 治疗方法。 公共健康相关性：这项研究将提高我们对反式活性 DNA 结合蛋白 43 (TDP-43) 在阿尔茨海默病和额颞叶变性中作用的理解。更好地了解 TDP-43 的作用对于开发这两种疾病的靶向治疗非常重要。阿尔茨海默病和额颞叶变性影响着超过 500 万美国人。