Understanding the role of TDP-43 in Alzheimer's disease and FTLD

了解 TDP-43 在阿尔茨海默病和 FTLD 中的作用

• 批准号: 9132162
• 负责人: Keith A Josephs
• 金额: $ 32.49万
• 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 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132162
• 关键词: Accounting; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Atrophic; Attention; Autopsy; Brain; Cessation of life; Characteristics; Clinic; Clinical; Clinical Data; Cognition; DNA-Binding Proteins; Deposition; Frequencies; Goals; Guidelines; Health; Hippocampus (Brain); Image; Immunohistochemistry; Impaired cognition; International; Lewy Bodies; MRI Scans; Measures; Memory; Memory Loss; Minnesota; Modeling; Molecular Target; N-terminal; Neocortex; Nerve Degeneration; Neurofibrillary Tangles; Outcome; Pathology; Play; Probability; Process; Proteins; Public Health; Recruitment Activity; Role; Scheme; Staging; Statistical Models; Vascular Diseases; Work; abstracting; base; cerebral atrophy; cognitive performance; cohort; gray matter; hippocampal atrophy; hippocampal sclerosis; illness length; improved; link protein; morphometry; neocortical; neuroimaging; neuropsychological; protein TDP-43; response; tau Proteins; therapeutic target

 DESCRIPTION (provided by applicant): In the first cycle of our R01 we demonstrated that the transactive response DNA binding protein of 43 kDa (TDP-43) influences memory loss and hippocampal atrophy in Alzheimer's disease (AD). This showed that TDP-43 plays a key role in neurodegeneration in AD and represents an important new treatment target for AD. This work, however, was limited to subjects with advanced neuropathological stages of AD. If treating AD is going to be successful, there needs to be advancement in our understanding of how TDP-43 interacts with the other AD associated proteins of tau and beta-amyloid (Aß) to affect neurodegeneration across the entire spectrum of AD neuropathologic changes. The primary goal of our second cycle is therefore to determine how TDP-43, tau and Aß interact to account for neurodegeneration across all levels of AD neuropathologic changes. We aim to investigate the relationship between the frequency, burden and topographic distribution of TDP-43 and the topographic distributions of tau and Aß, and assess how these three proteins interact and influence clinical, neuropsychological and neuroimaging outcomes. We also aim to investigate whether neurodegeneration in AD is dependent on the ratio of C to N terminal TDP-43 specie, or TDP-43 subtype (A- D). To accomplish our aims we will perform pathological analyses on a cohort of 768 cases that have been prospectively recruited and autopsied between 1/1/2000 and 12/31/2013 at Mayo Clinic, Rochester, Minnesota. All 768 cases have already undergone a standard neuropathological assessment and been assigned a Braak neurofibrillary tangle stage measuring the distribution of tau deposition. For the renewal, we will perform Thal staging to assess Aß distribution on all 768 cases. TDP-43 immunohistochemistry was already performed on 342 cases in the first cycle, and so for this cycle we will perform TDP-43 immunohistochemistry on the remaining 426 cases to assess for 1) the presence of TDP-43, 2) TDP-43 distribution and assign each case a TDP-43 in AD stage, 3) TDP-43 burden in the hippocampus, 4) TDP-43 specie and 5) TDP-43 subtype. Clinical data will be abstracted for each case and tensor-based morphometry will be utilized to calculate volumes of the hippocampus and neocortex on all available MRI scans for each case. Statistical models will be utilized to assess the relationships between TDP-43, tau and Aß, accounting for other potentially confounding pathologies such as Lewy bodies, vascular disease and hippocampal sclerosis, and their relationship to cognitive impairment and brain atrophy across the AD neuropathologic spectrum. Ultimately, we aim to generate a model demonstrating how TDP-43, tau and Aß influence hippocampal and neocortical atrophy with disease duration. Findings from this R01 will significantly improve understanding of how these three potential molecular targets interact to influence the AD neurodegenerative process. Given that these proteins currently have the greatest potential as therapeutic targets for the treatment of AD, our R01 has potential for significant public health impact.

 描述（由适用提供）：在我们R01的第一个周期中，我们证明了43 kDa（TDP-43）的交易反应DNA结合蛋白会影响阿尔茨海默氏病（AD）中的记忆丧失和海马萎缩。这表明TDP-43在AD中的神经变性中起关键作用，并且代表了AD的重要新治疗靶标。但是，这项工作仅限于具有AD的高级神经病理学阶段的受试者。如果处理AD将是成功的，那么我们对TDP-43如何与TAU和β-淀粉样蛋白（Aß）的其他AD相关蛋白相互作用的理解需要进步，以影响整个AD神经病理学变化的神经变性。因此，我们第二个周期的主要目标是确定TDP-43，TAU和Aß如何相互作用，以说明AD神经病理学变化的所有级别的神经变性。我们旨在研究TDP-43的频率，烧伤和地形分布与Tau和Aß的地形分布之间的关系，并评估这三种蛋白质如何相互作用并影响临床，神经心理学和神经影像学结果。我们还旨在研究AD中的神经退行性变化是取决于C与N端子TDP-43 Specie的比率，还是TDP-43亚型（A- D）。为了实现我们的目标，我们将对768例案件进行病理分析，这些病例已被前瞻性地招募和尸检在2000年1月1日至2013年12月31日在明尼苏达州罗切斯特的Mayo Clinic。所有768例病例都已经理解了标准的神经病理评估，并分配了测量Tau沉积分布的Braak神经纤维缠结阶段。对于续订，我们将执行Thal分阶段以评估所有768例病例的Aß分布。 TDP-43在第一个周期已经在342例中进行了TDP-43免疫组织化学，因此，在本周期中，我们将对其余的426个病例进行TDP-43免疫化学，以评估1）TDP-43，2）TDP-43的存在，2）TDP-43分布并分配了每种情况，并分配了TDP-43 a tdp-43 a a tdp-43 TDP-43 Specie和5）TDP-43亚型。对于每种情况，将对每种情况的临床数据进行摘要，并将利用基于张量的形态计算每种情况的所有可用MRI扫描中海马和新皮层的体积。统计模型将用于评估TDP-43，TAU和Aß之间的关​​系，这是考虑其他潜在混杂的病理，例如Lewy身体，血管疾病和海马硬化，以及它们与AD神经病理学谱系的认知损伤和脑萎缩的关系。最终，我们旨在生成一个模型，以证明TDP-43，TAU和Aß如何影响海马和新皮质萎缩，并具有疾病持续时间。该R01的发现将显着提高对这三个潜在分子靶标如何相互作用以影响AD神经退行性过程的理解。鉴于这些蛋白质目前作为治疗AD治疗的治疗靶标具有最大的潜力，因此我们的R01具有重大的公共卫生影响。