Concordance of TDP-43 Inclusions with Cortical Atrophy and Clinical Phenotype

描述（由申请人提供）：以异常包涵体形式的错误折叠蛋白质聚集是许多神经退行性疾病的共同特征。这些内含物与神经突触丧失的确切关系尚不完全清楚，特别是 额颞叶变性（FTLD）。本研究的主要目的是阐明转录激活反应元件DNA结合蛋白-43（TDP- 43）包涵体与FTLD中神经元死亡之间的关系。这一点很重要，因为FTLD-TDP可以说是FTLD最常见的形式，并可能导致萎缩部位和临床表型的令人困惑的异质性。虽然在过去的几年里，FTLD-TDP的遗传学和细胞生物学取得了令人眼花缭乱的进展，但有关TDP-43包涵体的区域分布及其与疾病表型的关系的定量信息在文献中却非常缺乏。我们建议将我们的研究建立在对一组独特的尸检标本中异常TDP-43沉淀物进行无偏体视学定量的基础上，这些尸检标本来自具有已知区域萎缩模式和临床表型的患者。中心目标将是推断这些标本中细胞死亡的假定原因。然后将在异常TDP-43沉淀物的转基因小鼠模型中测试将从该人类材料中出现的假设。该应用程序来自阿尔茨海默病中心（ADC），专注于FTLD和脑库，其中有118例FTLD的尸检病理特征病例，并提供详细的临床信息。我们将测试以下假设：1。TDP-43内含物密度的区域差异将反映临床表型、局灶性萎缩模式、神经元和突触损失的分布， 和炎症标志物的浓度。2.皮质TDP-43过表达小鼠将表现出与皮质TDP-43内含物积累、神经元和突触损失以及炎性标志物浓度相关的年龄依赖性行为异常。3.海马齿状回的已知回路及其对TDP-43内含物的偏好将揭示具有FTLD-TDP病理学的人脑和条件性TDP-43过表达小鼠中神经病理学的潜在顺行轴树突和跨突触传播。将使用组织学、免疫组织化学、无偏体视学定量方法和光密度测量来解决这些假设。拟议的研究将产生与TDP-43阳性内含物的贡献相关的信息，不仅对疾病表型和萎缩，而且对潜在的神经元和突触损失。从长远来看，这些信息将与靶向TDP-43的治疗方法相关。

DESCRIPTION (provided by applicant): Aggregation of misfolded proteins in the form of abnormal inclusions is a common feature of numerous neurodegenerative diseases. The exact relationship of these inclusions to the neurosynaptic loss is incompletely understood, particularly in frontotemporal lobar degeneration (FTLD). The major goal of this proposal is to clarify the relationship between transactivation response element DNA binding protein-43 (TDP- 43) inclusions and neuronal death in FTLD. This is important because FTLD-TDP is arguably the most frequent form of FTLD and can lead to a bewildering heterogeneity of atrophy sites and clinical phenotypes. While the past few years have witnessed dazzling advances in the genetics and cellular biology of FTLD-TDP, quantitative information on the regional distribution of TDP-43 inclusions and its relationship with disease phenotype is glaringly absent from the literature. We propose to base our investigation on the unbiased stereological quantification of abnormal TDP-43 precipitates in a unique set of autopsy specimens from patients with known patterns of regional atrophy and clinical phenotypes. The central goal will be to infer the putative causes of cell death in these specimens. The hypotheses that will emerge from this human material will then be tested in a transgenic mouse model of abnormal TDP-43 precipitates. The application comes from an Alzheimer's Disease Center (ADC) with a focus on FTLD and a brain bank that has 118 autopsied pathologically characterized cases of FTLD with detailed clinical information. We will test the following hypotheses: 1. Regional differences in densities of TDP-43 inclusions will mirror clinical phenotype, focal atrophy patterns, distribution of neuronal and synaptic loss, and concentrations of inflammatory markers. 2. Conditionally TDP-43 overexpressing mice will display age-dependent behavioral abnormalities related to accumulation of cortical TDP-43 inclusions, neuronal and synaptic loss and concentration of inflammatory markers. 3. The known circuitry of the hippocampal dentate gyrus and its predilection to TDP-43 inclusions will reveal potential anterograde axodendritic and transsynaptic spread of neuropathology in human brains with FTLD-TDP pathology and in conditionally TDP-43 overexpressing mice. Histological, immunohistochemical, unbiased stereological quantitative methods and optical density measures will be used to address these hypotheses. The proposed research will generate information relevant to the contribution of TDP-43-positive inclusions, not only to disease phenotype and atrophy, but also to the underlying neuronal and synaptic loss. In the long-run, this information will be relevant to therapeutic approaches targeting TDP-43.