Many neurodegenerative diseases (NDs) such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington’s disease, are characterized by the progressive accumulation of abnormal proteinaceous assemblies in specific cell types and regions of the brain, leading to cellular dysfunction and brain damage. Although animal- and in vitro-based studies of NDs have provided the field with an extensive understanding of some of the mechanisms underlying these diseases, findings from these studies have not yielded substantial progress in identifying treatment options for patient populations. This necessitates the development of complementary model systems that are better suited to recapitulate human-specific features of ND pathogenesis. Three-dimensional (3D) culture systems, such as cerebral organoids generated from human induced pluripotent stem cells, hold significant potential to model NDs in a complex, tissue-like environment. In this review, we discuss the advantages of 3D culture systems and 3D modeling of NDs, especially AD and FTD. We also provide an overview of the challenges and limitations of the current 3D culture systems. Finally, we propose a few potential future directions in applying state-of-the-art technologies in 3D culture systems to understand the mechanisms of NDs and to accelerate drug discovery.

许多神经退行性疾病 (NDs)，如阿尔茨海默病、帕金森病、额颞叶痴呆、肌萎缩侧索硬化症和亨廷顿病，其特征是异常蛋白质组装在特定细胞类型和大脑区域的进行性积累，导致细胞功能障碍和大脑损害。虽然动物和体外基于 ND 的研究为该领域提供了对这些疾病的一些潜在机制的广泛理解，这些研究的结果在确定患者群体的治疗方案方面没有取得实质性进展。这需要开发更适合概括 ND 发病机制的人类特异性特征的互补模型系统。三维 (3D) 培养系统，例如由人类诱导的多能干细胞产生的大脑类器官，具有在复杂的组织样环境中模拟 ND 的巨大潜力。在这篇综述中，我们讨论了 3D 培养系统和 ND 的 3D 建模的优势，尤其是 AD 和 FTD。我们还概述了当前 3D 培养系统的挑战和局限性。最后，