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

描述(申请人提供)：错误折叠的蛋白质以异常包涵体的形式聚集是许多神经退行性疾病的共同特征。这些包涵体与神经突触丢失的确切关系还不完全清楚，尤其是 额颞叶变性(FTLD)。本研究的主要目的是阐明FTLD中反式激活反应元件DNA结合蛋白-43(TDP-43)包涵体与神经元死亡的关系。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。尽管过去几年在FTLD-TDP的遗传学和细胞生物学方面取得了令人眼花缭乱的进展，但关于TDP-43包涵体的区域分布及其与疾病表型关系的定量信息在文献中明显缺乏。我们建议我们的研究基于对一组独特的尸检标本中异常TDP-43沉淀物的无偏向体视学定量，这些标本来自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。从这种人类材料中产生的假说将在TDP-43异常沉淀的转基因小鼠模型中进行测试。这项申请来自一家专注于FTLD的阿尔茨海默病中心(ADC)和一家脑库，该中心拥有118例具有病理特征的FTLD尸检病例，并提供详细的临床信息。我们将检验以下假设：1.TDP-43包涵体密度的地区差异将反映临床表型、局灶性萎缩模式、神经元和突触丢失的分布， 以及炎性标志物的浓度。2.条件性高表达TDP-43的小鼠表现出与年龄相关的行为异常，表现为皮质TDP-43包涵体积聚、神经元和突触丢失以及炎性标志物浓度升高。3.已知的海马齿状回环路及其对TDP-43包涵体的偏好，将揭示FTLD-TDP病理人脑和条件性TDP-43高表达小鼠神经病理的顺行、轴突和跨突触扩散。组织学、免疫组织化学、无偏的体视学定量方法和光密度测量将用于解决这些假说。这项拟议的研究将产生与TDP-43阳性包涵体的贡献相关的信息，不仅与疾病表型和萎缩有关，而且与潜在的神经元和突触丢失有关。从长远来看，这些信息将与针对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.