Synergistic Interaction of amyloid-beta and alpha-synuclein in Lewy body Dementia

无壁路易体痴呆中心(CWOW)的主要目标是了解淀粉样β蛋白(Aβ)和α-突触核蛋白(α-SYN)的协同作用，并确定遗传风险因素，如载脂蛋白E4，如何在LBD发病机制中起作用。使用来自梅奥诊所脑库的特征良好的尸检脑组织，CWow调查人员将探索LBD中Aβ和α-SYN物种的遗传学、转录组学、蛋白质组学、脂质组学、结构、生化和功能。CWow有一个管理核心和一个神经病理学和生物化学核心，以及四个研究项目。行政核心将提供财政和科学监督、管理和报告职能。神经病理学和生化核心将为所有项目提供神经病理学特征良好的LBD脑样本和定量的内表型。这些研究项目由高素质的研究人员领导，他们专注于LBD的补充和基本方面。项目1将探索LBD临床和病理异质性的遗传相关性，以及来自单核测序的细胞特异性转录本数据，以建立网络分析，这将为潜在的疾病机制提供洞察。项目2将识别和验证LBD大脑中可能对LBD的独特病理特征重要的蛋白质和低丰富的生物活性脂类。项目3将使用最先进的冷冻-EM技术来表征LBD大脑中α-SYN和Aβ细丝的天然和分子结构，以对这种疾病中蛋白质聚集体的病因、毒性和传播产生新的见解。项目4将从死后大脑中分离和表征Aβ和α-SYN亚种，并使用细胞模型揭示导致疾病发病机制的中毒途径。我们预计，在资助期结束时，我们将在了解LBD独特的结构和分子特征以及Aβ和α-SYN之间的遗传和相互作用如何导致LBD的独特症状、进展和潜在病理方面取得重大进展。

The overarching goal of this proposed Lewy body dementia (LBD) center without walls (CWOW) is to understand synergistic interactions of amyloid-beta (Aβ) and alpha-synuclein (α-syn) and to determine how genetic risk factors, such as apolipoprotein E4, contribute to LBD pathogenesis. Using well-characterized postmortem brain tissue from the Mayo Clinic Brain Bank, CWOW investigators will probe genetics, transcriptomics, proteomics, lipidomics, structure, biochemistry, and function of Aβ and α-syn species in LBD. The CWOW has an Administrative Core and a Neuropathology and Biochemistry Core, as well as four research projects. The Administrative Core will provide fiscal and scientific oversight, management, and reporting functions. The Neuropathology and Biochemistry Core will provide neuropathologically well- characterized LBD brain samples and quantitative endophenotypes to all projects. The research projects are led by highly qualified investigators who focus on complementary and fundamental aspects of LBD. Project 1 will explore genetic correlates of clinical and pathologic heterogeneity of LBD, as well as cell-specific transcript data from single nuclei sequencing to build network analyses, which will provide insights into underlying disease mechanisms. Project 2 will identify and validate proteins and low-abundant bioactive lipid species in LBD brains that may be important to the unique pathologic signature of LBD. Project 3 will use state-of-the–art cryo-EM techniques to characterize the native and molecular structures of α-syn and Aβ filaments in LBD brain to generate novel insight into the etiology, toxicity and spreading of protein aggregates in this disease. Project 4 will isolate and characterize Aβ and α-syn subspecies from postmortem brains and use cellular models to reveal mechanistic insight into toxic pathways contributing to disease pathogenesis. We envision that, at the conclusion of the funding period, we will have made significant progress towards understanding unique structural and molecular features of LBD and how genetics and interactions between Aβ and α-syn contribute to the unique symptoms, progression, and underlying pathology of LBD.