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

 描述(申请人提供)：在我们的R01的第一个周期中，我们证明了43 kDa的反式反应DNA结合蛋白(TDP-43)影响阿尔茨海默病(AD)的记忆丧失和海马区萎缩。这表明TDP-43在AD的神经退行性变中起关键作用，是治疗AD的一个重要的新靶点。然而，这项工作仅限于晚期阿尔茨海默病的受试者。如果治疗AD要取得成功，我们需要在理解TDP-43如何与其他AD相关蛋白tau和β-淀粉样蛋白(A？)相互作用以影响整个AD神经病理变化的神经退行性变方面取得进展。因此，我们第二个周期的主要目标是确定TDP-43、tau和Aü如何相互作用来解释所有水平的AD神经病理变化中的神经退行性变。我们的目的是研究TDP-43的频率、负荷和地形分布与tau和Aü的地形分布之间的关系，并评估这三种蛋白是如何相互作用并影响临床、神经心理和神经影像结果的。我们还旨在研究AD的神经退行性变是否依赖于C/N末端TDP-43物种或TDP-43亚型(A-D)的比例。为了实现我们的目标，我们将对明尼苏达州罗切斯特市梅奥诊所2000年1月1日至2013年12月31日期间前瞻性招募和尸检的768例病例进行病理分析。所有768例患者都已经接受了标准的神经病理学评估，并被分配到Braak神经纤维缠绕阶段，测量tau沉积的分布。对于更新，我们将执行Thal分期来评估所有768例患者的A？分布。在第一个周期中，342例已经进行了TDP-43免疫组织化学染色，因此在这个周期中，我们将对剩余的426例进行TDP-43免疫组织化学检查，以评估1)TDP-43的存在，2)TDP-43的分布，并对每个病例在AD期进行TDP-43的分类，3)TDP-43在海马区的负荷，4)TDP-43的种类和5)TDP-43的亚型。每个病例的临床数据将被提取，基于张量的形态测量将被用来计算每个病例所有可用的MRI扫描上的海马体和新皮质的体积。统计模型将被用来评估TDP-43、tau和Aü之间的关系，考虑到其他潜在的混杂病理，如路易小体、血管疾病和海马硬化症，以及它们与认知障碍和AD神经病理谱中的脑萎缩的关系。最终，我们的目标是建立一个模型，展示TDP-43、tau和A？如何影响海马区和新皮质萎缩与病程的关系。R01的发现将显著提高对这三个潜在分子靶点如何相互作用影响AD神经退变过程的理解。鉴于这些蛋白质目前最有潜力作为治疗AD的靶点，我们的R01有可能对公众健康产生重大影响。

 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.