Network and cellular vulnerability to pathological protein progression

项目摘要/摘要 美国目前有超过650万人患有进行性神经退行性阿尔茨海默氏症 疾病(AD)和相关的痴呆，包括路易体痴呆(DLB)，但没有治疗方法来阻止他们 提供进阶服务。大脑中聚集蛋白的存在(tau、淀粉样蛋白β(Aβ)和α- 突触核蛋白)被认为是疾病的基础，这些疾病的临床表现重叠与 存在一种以上类型的病理。影响蜂窝和网络脆弱性的因素 每一种单独的病理或共同发生的病理并不是很好地理解。正确理解 共同病理学背景下的脆弱性对于新疾病的发展和评估是必要的-- 修改治疗方法。 这个项目将测试细胞内α-突触核蛋白和tau病理进展是有联系的假设。 受神经解剖连接的影响，但受网络和细胞水平的脆弱性的影响。网络和蜂窝级别 脆弱性还可能受到其他因素的影响，例如是否存在共病，包括 细胞外淀粉样蛋白β(Aβ)斑块。为了验证这一假设，我们将追求以下目标：(I)进步 α-突触核蛋白和tau蛋白的病理在野生型小鼠身上被定位，这些小鼠具有单一或多种高水平的病理 使用注册到常见神经解剖图谱的分辨率和进展的网络参数将是 使用计算模型进行评估(具体目标1)；将进行定量病理学和网络分析 用于评估β斑块对α突触核蛋白的发展、传播和网络脆弱性的影响 和tau在表达人tau并形成β斑块的敲入小鼠中的共同病理，并呈时间依赖性 方式(特定目标2)；人类AD脑、DLB脑和小鼠共同病理脑的空间转录 将被用来确定易受α-突触核蛋白或tau病理影响的神经元的独特分子特征。 漏洞特征将用原位杂交-免疫荧光相结合的方法进行验证 利用网络脆弱性和区域基因表达来开发和评估人类共同病理模型 进展作为了解疾病进展和评估治疗效果的资源(特定 目标3)。 这项拟议的研究有望提高我们对共同死亡的时空进程的理解。 并开发改进的工具来评估可能减缓的新治疗策略的有效性 神经退行性疾病的进展。

PROJECT SUMMARY/ABSTRACT Over 6.5 million people in the United States currently live with progressive neurodegenerative Alzheimer’s disease (AD) and related dementias including dementia with Lewy bodies (DLB), yet no treatments to stop their progression are available. The presence of aggregated proteins in the brain (tau, amyloid β (Aβ), and α- synuclein) is thought to underlie disease, and clinical overlap in presentation of these diseases associates with the presence of more than one type of pathology. The factors influencing cellular and network vulnerability to each individual pathology or co-occurring pathologies are not well-understood. A proper understanding of vulnerability in the context of co-pathologies is necessary for the development and evaluation of novel disease- modifying treatments. This project will test the hypothesis that progression of intracellular α-synuclein and tau pathologies are bound by neuroanatomical connectivity but influenced by network and cell-level vulnerability. Network and cell-level vulnerability may also be influenced by additional factors such as the presence of co-pathologies, including extracellular amyloid β (Aβ) plaques. To test this hypothesis, the following aims will be pursued: (i) progression of α-synuclein and tau pathologies will be mapped in wildtype mice bearing single or multiple pathologies at high resolution using registration to a common neuroanatomical atlas, and network parameters of progression will be assessed with computational modeling (Specific Aim 1); quantitative pathology and network analysis will be utilized to assess the impact of Aβ plaques on the development, spread, and network vulnerability to α-synuclein and tau co-pathology in knock-in mice that express human tau and develop Aβ plaques and in a time-dependent manner (Specific Aim 2); spatial transcriptomics of human AD brain, DLB brain, and mouse co-pathology brain will be used to determine unique molecular signatures of neurons vulnerable to α-synuclein or tau pathologies. Vulnerability signatures will be validated with combined in situ hybridization-immunofluorescence and integrated with network vulnerability and regional gene expression to develop and evaluate a model of human co-pathology progression as a resource for understanding disease progression and evaluating therapeutic efficacy (Specific Aim 3). The proposed research is expected to improve our understanding of the spatiotemporal progression of co- pathologies and to develop improved tools to evaluate efficacy of novel therapeutic strategies that could slow the progression of neurodegenerative diseases.