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

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，因此是一个主要的健康问题。这两种疾病都影响老年人，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）有关。我们最近发现，几乎50%的AD患者的脑细胞中也有TDP-43蛋白沉积。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。然而，目前尚不清楚TDP-43在AD中的作用是否与其在FTLD中的作用不同，以及TDP-43在AD中的沉积是否具有任何临床意义。本R 01的主要目的是更好地了解TDP-43在FTLD和AD中的作用和意义。为了实现这一目标，我们将研究一个大型队列的AD和FTLD的尸检确诊病例，这些病例是通过我们的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蛋白的相关性和蛋白片段化。然后将确定病理特征与临床和成像特征之间的关联。将使用最先进的自动成像技术（包括基于体素的形态测量和基于图谱的分割）研究成像-病理学关联。这些方法将由一组世界知名的科学家执行，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治疗方法。 公共卫生相关性：本研究将有助于我们进一步了解反式DNA结合蛋白43（TDP-43）在阿尔茨海默病和额颞叶变性中的作用。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退化影响了超过500万美国人。

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.