Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease

解读阿尔茨海默病神经网络功能障碍的多因素病因

• 批准号: 10670331
• 负责人: YADONG HUANG
• 金额: $ 465.72万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670331
• 关键词: Address; Algorithms; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Amino Acid Sequence; Amino Acid Substitution; Amyloid beta-Protein; Apolipoprotein E; Apolipoproteins; Autopsy; Behavior; Behavioral; Biochemical; Bioinformatics; Biological Assay; Brain; Cell Nucleus; Cells; Cognitive deficits; Communities; Complex; Data; Data Science Core; Data Set; Databases; Development; Disease; Disease Progression; Electrophysiology (science); Ensure; Etiology; Experimental Designs; Functional disorder; Goals; Histopathology; Human; Hyperactivity; Impaired cognition; Infection; Interneurons; Intervention; Lead; Link; Modeling; Molecular; Mus; Nature; Neuroglia; Neurons; Neurosciences; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Protein Isoforms; Public Health; Research; Research Activity; Role; Statistical Models; Stress; System; Systems Biology; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Validation; Virulence Factors; apolipoprotein E-4; behavior test; brain dysfunction; brain tissue; cell type; cohort; data harmonization; diverse data; drug development; epigenomics; epileptiform; experimental study; familial Alzheimer disease; human data; human tissue; improved; in vivo; innovation; insight; knock-down; mouse model; network dysfunction; neural network; neuromechanism; neuropathology; neurophysiology; novel; novel strategies; novel therapeutic intervention; overexpression; prevent; programs; research and development; tau Proteins; transcriptomics; working group

OVERALL – SUMMARY Alzheimer’s disease (AD) is a major unresolved public health problem. Efforts to prevent or stall this disease have failed, in good part because of inadequate understanding of its complex pathogenesis. Mounting evidence suggest that neural network dysfunction may underlie or promote AD-related cognitive deficits and contribute to disease progression. Yet, the causes and consequences of this dysfunction and the therapeutic potential of counteracting it remain sorely understudied. Therefore, the overarching goal of this program project is to decode the multifactorial etiology of AD-related neural network dysfunction and to leverage the novel mechanistic insights we will gain toward the development of better therapeutic strategies. Through collaborative interactions among four projects and two cores, our program will use systems neuroscience (neurophysiology and behavior) in combination with systems biology (single-cell transcriptomics and epigenomics), as well as neuropathology and improved mouse models, to determine how copathogenic interactions among apolipoprotein (apo) E4, amyloid-b (Ab), and tau cause neural network dysfunctions and cognitive decline in AD. An Administrative Core will coordinate all activities. Projects 1–3 will use novel mouse models of sporadic and familial AD to study interactions of different apoE isoforms with wildtype (WT) human tau (Project 1) or APP/Ab (Project 2), or among apoE4, Ab, and tau that is WT or bears disease-associated amino acid substitutions (Project 3). Project 4 will carry out single-nucleus transcriptomic and epigenomic analyses on postmortem brain tissues from deeply phenotyped human AD cases to gain novel insights into the multifactorial etiology of the human condition, validate leads from mouse studies, and encourage backtranslation into the models. An Integrative Data-Science Core will help us integrate results from all projects through innovative statistical modeling. This approach will reveal which aspects of human AD are most faithfully reproduced in the mouse models and help establish the causal drivers of cell-specific alterations in the human tissues, increasing the mechanistic resolving power of the latter studies. Therapeutic interventions in mouse models will determine whether reducing apoE4 expression in specific cell types can block copathogenic effects of apoE4 and tau on brain functions (Project 1), modulating the activity of specific interneurons can counteract copathogenic effects of apoE4 and APP/Ab (Projects 2 and 4), and knocking down tau can prevent and reverse brain dysfunction in models expressing all three pathogenic factors (Project 3). Through these highly cohesive efforts, our program will dissect the multifactorial interactions among AD-related pathogenic factors, define their relative contributions to the complex pathogenesis of brain dysfunctions, and help distinguish among neuropathological alterations that cause, result from, or are coincidental to neural network dysfunctions and cognitive decline. Sharing the diverse data sets we will generate and disseminating the novel integrative approaches we plan to develop for their analysis could enhance the progress of many other groups working in AD research and drug development or biomedicine in general.

总体-摘要 阿尔茨海默病（AD）是一个尚未解决的重大公共卫生问题。预防或阻止这种疾病的努力 失败了，很大程度上是因为对其复杂的发病机制缺乏了解。越来越多的证据 提示神经网络功能障碍可能是AD相关认知缺陷的基础或促进， 疾病进展。然而，这种功能障碍的原因和后果以及 对抗它的方法还没有被充分研究。因此，本项目的首要目标是解码 AD相关神经网络功能障碍的多因素病因学，并利用新的机制 我们将获得更好的治疗策略的发展。通过协作互动 在四个项目和两个核心中，我们的项目将使用系统神经科学（神经生理学和行为学） 结合系统生物学（单细胞转录组学和表观基因组学）以及神经病理学 和改进的小鼠模型，以确定载脂蛋白（apo）E4， 淀粉样蛋白-b（Ab）和tau引起AD中的神经网络功能障碍和认知下降。行政核心 协调所有活动。项目1-3将使用散发性和家族性AD的新型小鼠模型进行研究 不同apoE亚型与野生型（WT）人tau（项目1）或APP/Ab（项目2）的相互作用，或 apoE 4、Ab和tau，其为WT或具有疾病相关的氨基酸取代（项目3）。项目4将 对死后脑组织进行单核转录组和表观基因组分析， 人类AD病例的表型以获得对人类病症的多因素病因学的新见解， 验证来自小鼠研究的线索，并鼓励反向翻译到模型中。综合数据科学 Core将通过创新的统计建模帮助我们整合所有项目的结果。这种方法将 揭示人类AD的哪些方面在小鼠模型中最忠实地再现，并帮助建立 人体组织中细胞特异性改变的因果驱动因素，提高了组织的机械分辨能力 后来的研究。在小鼠模型中的治疗干预将决定是否降低apoE 4表达， 特定的细胞类型可以阻断apoE 4和tau对脑功能的共同致病作用（项目1）， 特异性中间神经元的活性可以抵消apoE 4和APP/Ab的共致病作用（项目2和 4），敲低tau蛋白可以预防和逆转表达所有三种致病性 项目（3）。通过这些高度凝聚力的努力，我们的计划将剖析多因素的相互作用， 在AD相关的致病因素中，确定它们在脑的复杂发病机制中的相对贡献， 功能障碍，并帮助区分神经病理学改变的原因，结果，或 与神经网络功能障碍和认知能力下降相吻合分享我们将生成的各种数据集 传播我们计划为他们的分析开发的新的综合方法可以提高 在AD研究和药物开发或一般生物医学方面工作的许多其他小组的进展。