Understanding the functional impacts of Aβ variants in Alzheimer's disease with human brain organoids

了解 Aβ 变异对阿尔茨海默病与人脑类器官的功能影响

• 批准号: 10523682
• 负责人: ANDREAS S BOMMARIUS
• 金额: $ 233.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523682
• 关键词: 3-Dimensional; ATAC-seq; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; American; Amino Acid Sequence; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Biochemical; Biological Models; Brain; Cell Nucleus; Cell model; Cerebrum; Characteristics; Chromatin; Cryoelectron Microscopy; DNA methylation profiling; Data; Dementia; Deposition; Disease; Disease Progression; Epigenetic Process; Etiology; Event; Foundations; Gene Expression; Generations; Goals; Human; Immunotherapy; In Vitro; Infection; Insulin; Investigation; Isotopes; Kinetics; Link; Maps; Methods; Modeling; Molecular; Molecular Profiling; Nature; Nerve Degeneration; Neurodegenerative Disorders; Organoids; Pathogenesis; Pathogenicity; Pathologic; Pattern; Peptide Hydrolases; Peptides; Persons; Phase; Phenotype; Polymers; Polymorph; Population; Prealbumin; Proliferating; Property; Proteins; Research Priority; Resistance; Resolution; Role; Specificity; Spectroscopy, Fourier Transform Infrared; TREM2 gene; Therapeutic; Therapeutic Intervention; Time; To specify; Toxic effect; United States; Variant; abeta accumulation; aged; alpha synuclein; brain tissue; cell type; experimental study; familial Alzheimer disease; gene regulatory network; genome-wide; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; member; misfolded protein; multidisciplinary; nonhuman primate; pandemic disease; prion seeds; prion-like; protein aggregation; protein misfolding; reconstruction; response; risk variant; solid state nuclear magnetic resonance; stem cell model; targeted treatment; tau Proteins; transcriptome sequencing; transmission process

While the AD etiology remains largely unknown, with no effective strategy to arrest the relentless progression of the disease, current evidence connects amyloid-β (Aβ), a 40/42 amino acid peptide, to early disease progression. How folding of this peptide might create the heterogeneous assemblies (strains) that propagate as a prion-like infection throughout the brain remains a central question. Accordingly, we propose to connect the mechanisms of diversification and propagation of proteopathic Aβ strains to their biochemical manifestation to connect the structural foundation of strain patterns with disease etiology in human brain organoids. Because strains influence the pathogenic properties of disease etiology and because aggregated Aβ proteins may also govern therapeutic approaches to the diseases (such as immunotherapy), it is essential to structurally and functionally characterize what we now understand to be the dynamic nature of proteopathic Aβ propagons. In the current application, we will combine our complementary areas of expertise to analyze the assembly and propagation of Aβ strains with their impact in human brain organoids (Z. Wen), spectroscopic analyses of the dynamic assembly network members (D. Lynn), and with high- and low-resolution cryo-EM reconstructions (B. Liang) to define critical disease propagons. Our overarching hypothesis is that the multidimensional dynamics of Aβ assemblies define dynamic kinetic stability underlying the pathobiology of the self-perpetuating amyloid strains of AD. First, we will identify strain-specific patterns of Aβ intracellular formation and propagation to correlate the molecular foundations of structural differences among Aβ strains (Aim 1). Second, we will determine the biochemical manifestation of Aβ strains and elucidate the underlying mechanisms by which aberrant strains function in the human cortical organoid model (Aim 2). Lastly, we will delineate the molecular signatures associated with Aβ strains in human cortical organoids (Aim 3). By combining the advanced human induced pluripotent stem cell technology with comprehensive structural and functional analyses, our investigation will reveal key structural features underlying the propagation of misfolded protein aggregates in Alzheimer’s disease, allowing us ultimately to identify early neurodegenerative AD etiology targets for therapeutic intervention.

尽管 AD 的病因在很大程度上仍不清楚，也没有有效的策略来阻止 AD 的无情进展。 目前的证据表明淀粉样蛋白-β (Aβ)（一种 40/42 氨基酸肽）与早期疾病进展有关。 这种肽的折叠如何产生异质组装体（菌株），并以类朊病毒的形式传播 整个大脑的感染仍然是一个中心问题。因此，我们建议将这些机制联系起来 蛋白质病 Aβ 菌株的多样化和繁殖及其生化表现，以将 人脑类器官中具有疾病病因学的应变模式的结构基础。因为应变影响 疾病病因学的致病特性，并且因为聚集的 Aβ 蛋白也可能控制治疗 针对疾病的方法（例如免疫疗法），有必要从结构和功能上表征 我们现在所理解的是蛋白病 Aβ 繁殖体的动态性质。在当前的应用程序中，我们 将结合我们互补的专业知识领域来分析 Aβ 菌株的组装和繁殖 它们对人脑类器官的影响（Z. Wen），动态组装网络的光谱分析 成员 (D. Lynn)，并使用高分辨率和低分辨率冷冻电镜重建 (B. Liang) 来定义关键 疾病传播者。我们的首要假设是 Aβ 组装体的多维动力学定义了 AD 自我永存淀粉样蛋白菌株病理学的动态动力学稳定性。首先，我们将 识别 Aβ 细胞内形成和传播的菌株特异性模式，以将分子 Aβ 菌株之间结构差异的基础（目标 1）。其次，我们要确定生化指标 Aβ 菌株的表现并阐明异常菌株在 Aβ 菌株中发挥作用的潜在机制 人类皮质类器官模型（目标 2）。最后，我们将描述与 Aβ 相关的分子特征 人类皮质类器官中的菌株（目标 3）。结合先进的人类诱导多能干细胞 通过全面的结构和功能分析技术，我们的研究将揭示关键结构 阿尔茨海默病中错误折叠蛋白质聚集体传播的特征，使我们能够 最终确定早期神经退行性 AD 病因学目标以进行治疗干预。