小柯机器人

美国索尔克生物研究所Fred H. Gage、Jerome Mertens等研究人员合作发现，阿尔茨海默症患者的诱导神经元具有年龄依赖的成熟神经元命运不稳定性。这一研究成果于2021年4月27日在线发表在国际学术期刊《细胞—干细胞》上。

通过使用阿尔茨海默症（AD）患者成纤维细胞直接转化为诱导神经元（iNs），研究人员获得了一个年龄等效的神经元模型。患者来源的iNs表现出强大的神经元转录组特征，其特征在于成熟神经元特性的下调以及未成熟和祖细胞样信号通路的上调。将iNs映射到纵向神经元分化的轨迹数据表明，AD iNs反映了以压力、细胞周期和去分化标记为特征的神经元发育不全。表观遗传分布图揭示了潜在的异常神经元状态，与恶性转化和年龄依赖性表观遗传侵蚀具有相似之处。

为了探究衰老的影响，研究人员获得了未显示与疾病相关转录组特征的年轻iPSC衍生神经元，其特征与表观遗传时钟和大脑个体发生一致，这表明成纤维细胞衍生的iN更能反映老年人脑阶段。这些发现将与AD相关的神经元变化确定为损害神经元身份的年龄相关细胞程序。

附：英文原文

Title: Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients

Author: Jerome Mertens, Joseph R. Herdy, Larissa Traxler, Simon T. Schafer, Johannes C.M. Schlachetzki, Lena Bhnke, Dylan A. Reid, Hyungjun Lee, Dina Zangwill, Diana P. Fernandes, Ravi K. Agarwal, Raffaella Lucciola, Lucia Zhou-Yang, Lukas Karbacher, Frank Edenhofer, Shani Stern, Steve Horvath, Apua C.M. Paquola, Christopher K. Glass, Shauna H. Yuan, Manching Ku, Attila Szücs, Lawrence S.B. Goldstein, Douglas Galasko, Fred H. Gage

Issue&Volume: 2021-04-27

Abstract: Sporadic Alzheimer’s disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.

DOI: 10.1016/j.stem.2021.04.004

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00161-2

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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