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

描述（由申请人提供）：错误折叠蛋白质以异常内含物的形式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损失的确切关系尚不完全清楚，特别是 额颞叶变性（FTLD）。该提案的主要目标是阐明反式激活反应元件 DNA 结合蛋白 43 (TDP-43) 内含物与 FTLD 中神经元死亡之间的关系。这很重要，因为 FTLD-TDP 可以说是 FTLD 最常见的形式，并且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 FTLD-TDP 的遗传学和细胞生物学取得了令人瞩目的进展，但文献中明显缺乏有关 TDP-43 内含物区域分布及其与疾病表型关系的定量信息。我们建议我们的研究基于对来自具有已知区域萎缩和临床表型模式的患者的一组独特尸检标本中异常 TDP-43 沉淀物的无偏立体学定量。中心目标是推断这些样本中细胞死亡的推定原因。从这种人类材料中得出的假设将在异常 TDP-43 沉淀的转基因小鼠模型中进行测试。该应用程序来自专注于 FTLD 的阿尔茨海默病中心 (ADC) 和一个脑库，该脑库拥有 118 个具有详细临床信息的 FTLD 尸检病理特征病例。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. 有条件地过度表达 TDP-43 的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症标记物浓度相关的年龄依赖性行为异常。 3. 已知的海马齿状回回路及其对 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突和跨突触传播。组织学、免疫组织化学、无偏立体学定量方法和光密度测量将用于解决这些假设。拟议的研究将产生与 TDP-43 阳性包含物的贡献相关的信息，不仅与疾病表型和萎缩有关，而且与潜在的神经元和突触损失有关。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.