Molecular and cellular underpinnings of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC)

项目摘要/摘要 43 kDa的晚期NC(边缘占优势的年龄相关反式反应DNA结合蛋白[TDP-43]) 脑病，一种最近被确认的TDP-43蛋白病，是第三种 阿尔茨海默病后痴呆的最主要原因神经病理改变(ADNC)和 脑血管疾病，占所有老年人痴呆症病例的15%-20%。遗传关联 我们小组和其他人的研究揭示了独特的、晚期NC特有的风险基因以及与其他人共享的风险基因 常见的导致痴呆症的蛋白质病。我们组的一项转录本研究表明内源性溶酶体 调节失调是晚期NC的重要病理生理过程。然而，分子和细胞 晚期-NC的基础在很大程度上仍然未知：我们甚至没有在体外/体内发展的知识 活体疾病模型或指定靶路径，因此，我们无法诊断、治疗或预防 已故-NC在活人中还没有。确定晚期NC潜在的分子和细胞变化是先决条件 发展可翻译的体外/体内疾病模型和确定生物标记物/治疗靶点。这 2022年NIH AD相关痴呆症(ADRD)峰会承认了严重的知识差距， 它提出了一个高度优先的建议，以调查与晚期北卡罗来纳州相关的分子变化。 因此，这项提议旨在定义晚期NC的转录、蛋白质组和细胞基础 在人类杏仁核，被认为是晚期NC起源的大脑区域。我们的中心假设是， 在杏仁核，内源性溶酶体失调，RNA代谢改变，神经胶质功能障碍和神经元丢失 这是晚期NC病理生理学的基础。为了检验中心假设，我们建议生成和分析 转录组、蛋白质组和单核多组体(转录组和染色质可获得性)数据来自 具有广泛特征的宗教教团研究和Rush的死后杏仁核样本 记忆和老龄化项目参与者(n=480)。我们将追求以下三个具体目标：一是 确定晚期NC的转录基础。第二，我们将鉴定蛋白质组签名 晚期-北卡罗来纳州。第三，我们将定义后期北卡罗来纳州的单细胞格局。我们将使用统计建模 推断因果关系的方法。我们将考虑特定性别的影响以及 在整个研究过程中并发ADNC病理。该项目的预期结果将提名蛋白质 生物标记物的靶点和定义北冰洋晚期看似合理的上下游事件。这些结果将指导 我们未来的研究将在体外和可能在体内开发晚期NC模型，并最终达到靶向 治疗学。大规模的杏仁核多组体数据将与科学界广泛共享，以 支持众多ADRD研究项目，确保对神经退行性变产生重大持久影响 研究远远超出了这一提议。因此，这个项目有可能从根本上提高我们的能力 诊断、治疗并最终预防痴呆症，包括晚期痴呆。

PROJECT SUMMARY/ABSTRACT LATE-NC (limbic-predominant age-related transactive response DNA-binding protein of 43 kDa [TDP-43] encephalopathy neuropathological change), a recently recognized form of TDP-43 proteinopathy, is the third most impactful cause of dementia following Alzheimer’s disease neuropathologic change (ADNC) and cerebrovascular disease, accounting for 15-20% of all dementia cases in older adults. Genetic association studies by our group and others revealed unique, LATE-NC-specific risk loci as well as those shared with other common dementia-causing proteinopathies. A transcriptomic study from our group implicated endo-lysosomal dysregulation as a crucial pathophysiologic process underlying LATE-NC. However, molecular and cellular underpinnings of LATE-NC remain largely unknown: we do not even have the knowledge to develop in vitro/in vivo disease models or nominate target pathways, and as a result, we cannot diagnose, treat, or prevent LATE-NC in living persons yet. Defining molecular and cellular changes underlying LATE-NC is a prerequisite to developing translatable in vitro/in vivo disease models and identifying biomarker/therapeutic targets. This critical knowledge gap has been acknowledged by the NIH AD-Related Dementias (ADRD) Summit in 2022, which made a high-priority recommendation to investigate molecular changes associated with LATE-NC. Therefore, this proposal aims to define the transcriptomic, proteomic, and cellular underpinnings of LATE-NC in the human amygdala, the brain region where LATE-NC is thought to originate. Our central hypothesis is that, in the amygdala, endo-lysosomal dysregulation, altered RNA metabolism, glial dysfunction, and neuronal loss underlie LATE-NC pathophysiology. To test the central hypothesis, we propose to generate and analyze transcriptomic, proteomic, and single-nucleus multiome (transcriptome and chromatin accessibility) data from the post-mortem amygdala samples from the extensively characterized Religious Orders Study and Rush Memory and Aging Project participants (n=480). We will pursue the following three specific aims: First, we will determine the transcriptomic underpinnings of LATE-NC. Second, we will identify the proteomic signature of LATE-NC. Third, we will define the single-cell landscape of LATE-NC. We will use statistical modeling approaches to infer causal relationships. We will consider sex-specific effects and the confounding effect of comorbid ADNC pathology throughout the study. The expected outcomes of this project will nominate protein biomarker targets and define plausible upstream and downstream events of LATE-NC. These results will guide our future studies to develop in vitro and possibly in vivo LATE-NC models and, eventually, targeted therapeutics. The large-scale amygdala multi-omic data will be broadly shared with the scientific community to support numerous ADRD research projects, ensuring a significant lasting impact in neurodegeneration research far beyond this proposal. Therefore, this project has the potential to fundamentally improve our ability to diagnose, treat, and ultimately prevent dementia, including LATE.