脑类器官已成为研究人类大脑发育、疾病建模和药物测试的重要工具。然而，生成具有成熟神经元的大脑类器官非常耗时且通常不完整，限制了它们在研究阿尔茨海默病（AD）等与年龄相关的神经退行性疾病中的效用。在这里，我们报告了通过直接重编程从人类成纤维细胞生成 3D 大脑类器官，简单、高效且变异性降低。我们还证明，来自 APOE ε4 AD 患者成纤维细胞的诱导脑类器官捕获了与 APOE ε4 AD 相关的一些疾病特异性特征和病理。此外，APOE ε4 诱导的具有突变 APP 过度表达的脑类器官忠实地再现了 AD 相关病理的加速，提供了更具生理相关性和患者特异性的家族性 AD 模型。重要的是，转录组分析表明，APOE ε4 患者诱导的大脑类器官特异的基因集与 APOE ε4 死后 AD 大脑的基因集高度相似。总体而言，直接重编程诱导的大脑类器官为更有效和受控的神经退行性疾病建模研究提供了一种有前景的方法。版权所有 © 2024 Kim、Kim、Cho、An、Kang、Kim 和 Kim。

Brain organoids have become a valuable tool for studying human brain development, disease modeling, and drug testing. However, generating brain organoids with mature neurons is time-intensive and often incomplete, limiting their utility in studying age-related neurodegenerative diseases such as Alzheimer's disease (AD). Here, we report the generation of 3D brain organoids from human fibroblasts through direct reprogramming, with simplicity, efficiency, and reduced variability. We also demonstrate that induced brain organoids from APOE ε4 AD patient fibroblasts capture some disease-specific features and pathologies associated with APOE ε4 AD. Moreover, APOE ε4-induced brain organoids with mutant APP overexpression faithfully recapitulate the acceleration of AD-related pathologies, providing a more physiologically relevant and patient-specific model of familial AD. Importantly, transcriptome analysis reveals that gene sets specific to APOE ε4 patient-induced brain organoids are highly similar to those of APOE ε4 post-mortem AD brains. Overall, induced brain organoids from direct reprogramming offer a promising approach for more efficient and controlled studies of neurodegenerative disease modeling.Copyright © 2024 Kim, Kim, Cho, An, Kang, Kim and Kim.