Ji Yanru, Chen Xiaoling, Wang Zhen, Meek Connor Joseph, McLean Jenna Lillie, Yang Yang, Yuan Chongli, Rochet Jean-Christophe, Liu Fei, Xu Ranjie
Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA.
Purdue Institute for Integrative Neuroscience (PIIN), Purdue University, West Lafayette, IN, 47907, USA.
Mol Psychiatry. 2025 May 2. doi: 10.1038/s41380-025-03041-w.
Alzheimer's Disease (AD) is the most common cause of dementia, afflicting 55 million individuals worldwide, with limited treatment available. Current AD models mainly focus on familial AD (fAD), which is due to genetic mutations. However, models for studying sporadic AD (sAD), which represents over 95% of AD cases without specific genetic mutations, are severely limited. Moreover, the fundamental species differences between humans and animals might significantly contribute to clinical failures for AD therapeutics that have shown success in animal models, highlighting the urgency to develop more translational human models for studying AD, particularly sAD. In this study, we developed a complex human pluripotent stem cell (hPSC)-based vascularized neuroimmune organoid model, which contains multiple cell types affected in human AD brains, including human neurons, microglia, astrocytes, and blood vessels. Importantly, we demonstrated that brain extracts from individuals with sAD can effectively induce multiple AD pathologies in organoids four weeks post-exposure, including amyloid beta (Aβ) plaque-like aggregates, tau tangle-like aggregates, neuroinflammation, elevated microglial synaptic pruning, synapse/neuronal loss, and impaired neural network activity. Proteomics analysis also revealed disrupted AD-related pathways in our vascularized AD neuroimmune organoids. Furthermore, after treatment with Lecanemab, an FDA-approved antibody drug targeting Aβ, AD brain extracts exposed organoids showed a significant reduction of amyloid burden, along with an elevated vascular inflammation response. Thus, the vascularized neuroimmune organoid model provides a unique opportunity to study AD, particularly sAD, under a pathophysiological relevant three-dimensional (3D) human cell environment. It also holds great promise to facilitate AD drug development, particularly for immunotherapies.
阿尔茨海默病（AD）是痴呆最常见的病因，全球有5500万人受其折磨，且可用治疗方法有限。目前的AD模型主要聚焦于家族性AD（fAD），其由基因突变所致。然而，用于研究散发性AD（sAD）的模型严重受限，sAD占AD病例的95%以上，且无特定基因突变。此外，人类与动物之间的基本物种差异可能是导致在动物模型中显示成功的AD疗法临床失败的重要原因，这凸显了开发更多用于研究AD，尤其是sAD的转化性人类模型的紧迫性。在本研究中，我们构建了一种基于人类多能干细胞（hPSC）的复杂血管化神经免疫类器官模型，其中包含人类AD大脑中受影响的多种细胞类型，包括人类神经元、小胶质细胞、星形胶质细胞和血管。重要的是，我们证明，sAD个体的脑提取物在暴露四周后可有效诱导类器官出现多种AD病理变化，包括淀粉样β（Aβ）斑块样聚集体、tau缠结样聚集体、神经炎症、小胶质细胞突触修剪增加、突触/神经元丢失以及神经网络活动受损。蛋白质组学分析还揭示了我们的血管化AD神经免疫类器官中与AD相关的通路紊乱。此外，在用美国食品药品监督管理局（FDA）批准的靶向Aβ的抗体药物Lecanemab治疗后，暴露于AD脑提取物的类器官显示淀粉样蛋白负担显著降低，同时血管炎症反应增强。因此，血管化神经免疫类器官模型为在病理生理相关的三维（3D）人类细胞环境下研究AD，尤其是sAD提供了独特的机会。它还有望促进AD药物开发，特别是免疫疗法的开发。
