Accelerating the in vitro emulation of Alzheimer's disease-associated phenotypes using a novel 3D blood-brain barrier neurosphere co-culture model.
Accelerating the in vitro emulation of Alzheimer's disease-associated phenotypes using a novel 3D blood-brain barrier neurosphere co-culture model.
复制标题
使用新型3D血脑屏障神经球共培养模型加速阿尔茨海默病相关表型的体外仿真
DOI：
10.3389/fbioe.2023.1251195
复制
发表时间：
2023
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
--
作者：
阿尔茨海默病等神经退行性疾病临床试验的高失败率与当前基于动物的疾病模型的预测有效性不足有关。这使得对能够在体外模拟关键病理表型的替代性、基于人类的模型的需求日益增加。在这里，一个三维阿尔茨海默病模型是使用一个区室化的微流体装置开发的，该装置将人类血脑屏障的自组装微血管网络与来自阿尔茨海默病特异性神经祖细胞的神经球相结合。为了缩短微流体共培养时间，在引入微流体装置之前，将神经球预分化21天以表达阿尔茨海默病特异性病理表型。与死后研究和阿尔茨海默病体内模型一致，在与预分化的阿尔茨海默病特异性神经球共培养7天后，三维血脑屏障网络表现出屏障通透性和形态的显著变化。此外，与阿尔茨海默病特异性微组织共培养的血管网络显示出局部β-淀粉样蛋白沉积。因此，通过将血脑屏障的微血管网络与预分化的神经球互连，所提出的模型具有在体外复制神经退行性疾病的关键神经血管表型的巨大潜力。
High failure rates in clinical trials for neurodegenerative disorders such as Alzheimer’s disease have been linked to an insufficient predictive validity of current animal-based disease models. This has created an increasing demand for alternative, human-based models capable of emulating key pathological phenotypes in vitro. Here, a three-dimensional Alzheimer’s disease model was developed using a compartmentalized microfluidic device that combines a self-assembled microvascular network of the human blood-brain barrier with neurospheres derived from Alzheimer’s disease-specific neural progenitor cells. To shorten microfluidic co-culture times, neurospheres were pre-differentiated for 21 days to express Alzheimer’s disease-specific pathological phenotypes prior to the introduction into the microfluidic device. In agreement with post-mortem studies and Alzheimer’s disease in vivo models, after 7 days of co-culture with pre-differentiated Alzheimer’s disease-specific neurospheres, the three-dimensional blood-brain barrier network exhibited significant changes in barrier permeability and morphology. Furthermore, vascular networks in co-culture with Alzheimer’s disease-specific microtissues displayed localized β-amyloid deposition. Thus, by interconnecting a microvascular network of the blood-brain barrier with pre-differentiated neurospheres the presented model holds immense potential for replicating key neurovascular phenotypes of neurodegenerative disorders in vitro.