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

虽然AD病因在很大程度上仍然未知，但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氨基酸的肽）与早期疾病进展有关。 这种肽的折叠是如何产生作为朊病毒样病毒传播的异质组装体（菌株）的？ 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 蛋白病性Aβ菌株的多样化和繁殖与其生化表现的关系， 人脑类器官中具有疾病病因的应变模式的结构基础。因为应变会影响 疾病病因学的致病特性，并且因为聚集的Aβ蛋白也可能支配治疗 为了更好地治疗疾病（如免疫治疗），必须在结构和功能上表征 我们现在所理解的是蛋白病Aβ传播的动态本质。在本申请中，我们 将联合收割机结合我们互补的专业领域，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.林恩），并与高分辨率和低分辨率冷冻EM重建（B。Liang）来定义临界 疾病传播。我们的首要假设是，Aβ组装的多维动力学定义了 动态动力学稳定性是AD的自永存淀粉样蛋白菌株的病理生物学基础。一是 确定Aβ细胞内形成和增殖的菌株特异性模式，以将分子生物学相关性 Aβ菌株之间结构差异的基础（目的1）。其次，我们将确定生物化学 Aβ菌株的表现，并阐明了异常菌株在A β菌株中发挥作用的潜在机制。 人皮质类器官模型（Aim 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）。通过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，我们的研究将揭示关键的结构 阿尔茨海默病中错误折叠蛋白聚集体传播的潜在特征， 最终确定治疗干预的早期神经退行性AD病因靶点。

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.