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

 描述（由申请人提供）：在我们的R 01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）的记忆丧失和海马萎缩。这表明TDP-43在AD的神经退行性变中起关键作用，并代表了AD的重要新治疗靶点。然而，这项工作仅限于AD晚期神经病理学阶段的受试者。如果治疗AD要取得成功，我们需要进一步了解TDP-43如何与其他AD相关的tau蛋白和β-淀粉样蛋白（A β）相互作用，以影响整个AD神经病理学变化范围内的神经变性。因此，我们第二个周期的主要目标是确定TDP-43、tau蛋白和Akt蛋白如何相互作用，以解释所有水平的AD神经病理学变化中的神经变性。我们的目的是研究TDP-43的频率，负荷和地形分布与tau和Akt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中的神经变性是否依赖于C端与N端TDP-43种类或TDP-43亚型（A-D）的比率。为了实现我们的目标，我们将对2000年1月1日至2013年12月31日在明尼苏达州罗切斯特的马约诊所前瞻性招募和尸检的768例病例队列进行病理学分析。所有768例病例都已经进行了标准的神经病理学评估，并被分配到Braak神经系统缠结阶段，测量tau沉积的分布。对于更新，我们将进行塔尔分期，以评估所有768例病例的April分布。在第一个周期中已经对342例病例进行了TDP-43免疫组织化学，因此对于这个周期，我们将对剩余的426例病例进行TDP-43免疫组织化学，以评估1）TDP-43的存在，2）TDP-43分布并在AD阶段中为每个病例分配TDP-43，3）海马中的TDP-43负荷，4）TDP-43种; 5）TDP-43亚型。将提取每例病例的临床数据，并使用基于张量的形态测量法计算每例病例所有可用MRI扫描的海马和新皮质体积。将利用统计模型评估TDP-43、tau和Ablation之间的关系，解释其他潜在混淆病理学，如路易体、血管疾病和海马硬化，以及它们与AD神经病理学谱中认知障碍和脑萎缩的关系。最终，我们的目标是生成一个模型，证明TDP-43，tau蛋白和Akt蛋白如何影响海马和新皮质萎缩与疾病的持续时间。R 01的发现将显著提高对这三种潜在分子靶点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的治疗靶点具有最大的潜力，我们的R 01具有显著的公共卫生影响的潜力。

 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.