来自携带 PSEN1/2 突变的阿尔茨海默病患者的脑类器官具有组织模式缺陷和发育改变。
Cerebral organoids derived from patients with Alzheimer's disease with PSEN1/2 mutations have defective tissue patterning and altered development.
发表日期：2023 Oct 20
作者：
Tereza Vanova, Jiri Sedmik, Jan Raska, Katerina Amruz Cerna, Petr Taus, Veronika Pospisilova, Marketa Nezvedova, Veronika Fedorova, Sona Kadakova, Hana Klimova, Michaela Capandova, Petra Orviska, Petr Fojtik, Simona Bartova, Karla Plevova, Zdenek Spacil, Hana Hribkova, Dasa Bohaciakova
来源：
Cell Reports
摘要：
在过去的二十年中，诱导多能干细胞（iPSC）已被广泛用于研究人类神经发育和疾病。特别是在阿尔茨海默病（AD）领域，人们在研究这种疾病背后的分子机制方面付出了巨大的努力。然后，随着 3D 神经元培养和脑类器官 (CO) 的出现，多项研究表明该模型可以充分模拟家族性和散发性 AD。因此，我们使用源自家族性 AD 患者的 iPSC 创建了 AD-CO 模型，并探讨了 AD 发病机制的早期事件和进展。我们的研究表明，源自具有 PSEN1(A246E) 或 PSEN2(N141I) 突变的三个 AD-iPSC 系的 CO 在体外形成了 AD 特异性标记物，但它们也发现了组织模式缺陷和发育改变。这些发现得到了单细胞测序数据的补充，证实了这一观察结果，并揭示了 AD-CO 中的神经元可能过早分化。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。
During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study human neural development and disease. Especially in the field of Alzheimer's disease (AD), remarkable effort has been put into investigating molecular mechanisms behind this disease. Then, with the advent of 3D neuronal cultures and cerebral organoids (COs), several studies have demonstrated that this model can adequately mimic familial and sporadic AD. Therefore, we created an AD-CO model using iPSCs derived from patients with familial AD forms and explored early events and the progression of AD pathogenesis. Our study demonstrated that COs derived from three AD-iPSC lines with PSEN1(A246E) or PSEN2(N141I) mutations developed the AD-specific markers in vitro, yet they also uncover tissue patterning defects and altered development. These findings are complemented by single-cell sequencing data confirming this observation and uncovering that neurons in AD-COs likely differentiate prematurely.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.