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

TDP-43 包涵体与皮质萎缩和临床表型的一致性

• 批准号: 10600105
• 负责人: CHANGIZ GEULA
• 金额: $ 66.79万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600105
• 关键词: Ablation; Alzheimer' s Disease; Anatomy; Apoptosis; Area; Autopsy; Behavior; Behavior assessment; Behavioral; Biology; Brain; Chemicals; Clinical; Cognition; DNA-Binding Proteins; Dementia; Dendritic Spines; Disease; Exposure to; Frontotemporal Lobar Degenerations; Gene Expression; Genetic; Gliosis; Goals; Hippocampus; Human; Immune; Investigation; Mediating; Methods; Microglia; Mus; Neurodegenerative Disorders; Neurology; Neurons; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phagocytosis; Play; Process; Production; Productivity; Prosencephalon; Proteins; Proteome; Research; Research Personnel; Resources; Response Elements; Role; Specificity; Specimen; Surveys; Synapses; Testing; Time; Tissues; Transactivation; Transgenic Mice; Transgenic Organisms; base; brain tissue; cerebral atrophy; clinical phenotype; density; dentate gyrus; design; disease phenotype; exosome; gray matter; hippocampal sclerosis; human disease; immune activation; misfolded protein; mouse model; neurochemistry; neuropathology; protein TDP-43; protein expression; synaptic pruning; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; white matter

Project Summary Aggregation and propagation of misfolded proteins in the form of abnormal inclusions is a common feature of numerous neurodegenerative diseases. A majority of brains with frontotemporal lobar degeneration (FTLD) are characterized by mislocalization and aggregation of transactivation response element DNA binding protein-43 (TDP-43) into insoluble inclusions. Given that TDP-43 is among the most recently identified pathologic precipitates, the goal of Cycle 1 of this project was to explore the relationship between TDP-43 inclusions, cellular alterations, cortical atrophy and disease phenotype in FTLD and in a conditionally transgenic mouse model expressing wild-type human (h) TDP-43 in the forebrain. We observed that density of TDP-43 inclusions, neuronal shrinkage, and density of activated microglia in cortical gray and white matter are concordant with patterns of cortical atrophy and disease phenotype and that TDP-43 inclusions may spread trans-synaptically. In TDP-43 transgenic mice, we confirmed regionally selective cortical atrophy, and progressive TDP-43 accumulation and inclusion formation, gliosis, apoptosis and behavioral alterations consistent with the pathologic and behavioral alterations in FTLD. Importantly, the density of activated microglia displayed the closest and most consistent relationship with cortical atrophy and disease phenotype in FTLD. Cycle 2 of this project builds upon the observations during Cycle 1 and will focus on the role of microglia / immune activation, including synaptic pruning as disease spreads. We will conduct a comprehensive survey of microglia / immune gene and protein expression changes in brains of FTLD and hTDP transgenic mice, will explore alterations in synapses and synaptic proteins in FTLD and potential role of microglia mediated pruning in synaptic loss, and will investigate the role of microglia generated exosomes in spread of TDP-43 pathology in the mouse model. We propose to base this investigation on rigorous quantitative methods, including unbiased stereological quantification and RNA sequencing (RNAseq) in a unique set of autopsy specimens with extensive clinical and pathological information and in a mouse model which recapitulates features of human disease. The specific aims of the proposed research will test the following hypotheses: Aim 1. FTLD- TDP and hTDP-43 transgenic mouse brains will display regionally selective alterations in microglia transcriptome and associated immune proteins. Aim 2. FTLD-TDP and hTDP-43 transgenic mice will display substantial, early and regionally specific loss of synapses that is due in part to abnormal synaptic pruning by microglia. Aim 3. hTDP-43 transgenic mice will display trans-synaptic spread of TDP-43 pathology over time in the hippocampus and microglia derived exosomes facilitate this spread in the hippocampus and across cortex. The proposed research will generate a great deal of information on the status of synapses and potential trans- synaptic spread of TDP pathology as well as the role of microglia in these processes and in immune alterations. The findings have the potential to illuminate pathways that can serve as therapeutic targets.

项目摘要 错误折叠的蛋白质以异常包涵体的形式聚集和繁殖是蛋白质的一个共同特征。 许多神经退行性疾病。大多数患有额颞叶变性（FTLD）的大脑 以反式激活反应元件DNA结合蛋白-43的错误定位和聚集为特征 （TDP-43）转化为不溶性内含物。鉴于TDP-43是最近发现的病理性 沉淀物，该项目的第1周期的目标是探索TDP-43夹杂物， FTLD和条件性转基因小鼠的细胞改变、皮质萎缩和疾病表型 在前脑中表达野生型人（h）TDP-43的模型。我们观察到TDP-43的密度 在皮质灰质和白色物质中， 与皮质萎缩和疾病表型的模式一致，TDP-43包涵体可能扩散 跨突触的在TDP-43转基因小鼠中，我们证实了区域选择性皮质萎缩， 进行性TDP-43蓄积和包涵体形成、神经胶质增生、细胞凋亡和行为改变 与FTLD的病理和行为改变一致。重要的是，激活的密度 小胶质细胞与皮质萎缩和疾病表型的关系最密切， FTLD。本项目的第2周期建立在第1周期的观察基础上，并将重点关注小胶质细胞的作用 /免疫激活，包括疾病传播时的突触修剪。我们将进行全面调查 FTLD和hTDP转基因小鼠脑中小胶质细胞/免疫基因和蛋白质表达的变化， 探索FTLD中突触和突触蛋白的改变以及小胶质细胞介导的修剪的潜在作用 在突触丢失中，并将研究小胶质细胞产生的外泌体在TDP-43病理扩散中的作用 在小鼠模型中。我们建议将这项研究建立在严格的定量方法基础上，包括 在一组独特的尸检标本中进行无偏体视学定量和RNA测序（RNAseq） 具有广泛的临床和病理学信息，并在小鼠模型中重现了 人类疾病拟议研究的具体目标将测试以下假设：目标1。FTLD- TDP和hTDP-43转基因小鼠脑中的小胶质细胞将显示区域选择性改变 转录组和相关免疫蛋白。目标二。FTLD-TDP和hTDP-43转基因小鼠将显示 大量的、早期的和区域特异性的突触丢失，这部分是由于 小胶质细胞目标3. hTDP-43转基因小鼠将显示TDP-43病理随时间的跨突触扩散， 海马体和小胶质细胞衍生的外来体促进海马体中和跨皮质的这种扩散。 这项拟议中的研究将产生大量关于突触状态和潜在跨膜的信息。 TDP病理学的突触扩散以及小胶质细胞在这些过程中的作用和在免疫中的作用。 改变。这些发现有可能阐明可以作为治疗靶点的途径。