Network and cellular vulnerability to pathological protein progression

项目总结/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病 疾病（AD）和相关痴呆，包括路易体痴呆（DLB），但没有治疗方法来阻止他们的行为。 进步是可用的。脑中聚集蛋白（tau蛋白、淀粉样蛋白β（Aβ）和α-淀粉样蛋白）的存在与脑中的蛋白质含量有关。 突触核蛋白）被认为是疾病的基础，这些疾病的临床重叠表现与 存在一种以上的病理类型。影响蜂窝和网络脆弱性的因素 每个单独的病理或共同发生的病理没有被很好地理解。正确了解 共同病理学背景下的脆弱性对于开发和评估新疾病是必要的- 修改治疗。 该项目将检验细胞内α-突触核蛋白和tau蛋白病理学的进展是结合在一起的假设 受神经解剖学连接的影响，但受网络和细胞水平脆弱性的影响。网络和单元级 脆弱性还可能受到其他因素的影响，如共同病理学的存在，包括 细胞外淀粉样β（Aβ）斑块。为了检验这一假设，将追求以下目标： α-突触核蛋白和tau病理将在高浓度下携带单一或多种病理的野生型小鼠中进行定位。 将使用配准到常见神经解剖图谱的分辨率和进展的网络参数， 通过计算建模（具体目标1）进行评估;将进行定量病理学和网络分析。 用于评估Aβ斑块对α-突触核蛋白的发育、扩散和网络脆弱性的影响 在表达人tau蛋白并形成Aβ斑块的基因敲入小鼠中， 人AD脑、DLB脑和小鼠共病理脑的空间转录组学 将用于确定易受α-突触核蛋白或tau病理影响的神经元的独特分子特征。 脆弱性特征将通过结合原位杂交-免疫荧光和整合 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学模型， 进展作为了解疾病进展和评估治疗疗效的资源（具体 目标3）。 这项研究有望提高我们对协同效应时空进程的理解， 并开发改进的工具来评估新的治疗策略的有效性， 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.