Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA; Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University Innsbruck, Tyrol, Austria.
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA; Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University Innsbruck, Tyrol, Austria; Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
Cell Stem Cell. 2021 Sep 2;28(9):1533-1548.e6. doi: 10.1016/j.stem.2021.04.004. Epub 2021 Apr 27.
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.
散发性阿尔茨海默病（AD）仅影响老年人。我们使用 AD 患者成纤维细胞直接转化为诱导神经元（iNs），生成了年龄相当的神经元模型。AD 患者来源的 iNs 表现出强烈的神经元转录组特征，其特征是成熟神经元特性下调和未成熟及祖细胞样信号通路上调。将 iNs 映射到纵向神经元分化轨迹数据表明，AD iNs 反映了一种低成熟的神经元特性，其特征是应激、细胞周期和去分化的标志物。表观遗传景观分析揭示了一种潜在的异常神经元状态，与恶性转化和年龄相关的表观遗传侵蚀具有相似性。为了探究衰老的参与，我们生成了再年轻化的 iPSC 衍生神经元，它们没有表现出明显的与疾病相关的转录组特征，这一特征与表观遗传时钟和大脑发生图谱一致，表明成纤维细胞衍生的 iNs 更能反映老年成人大脑阶段。我们的研究结果表明，AD 相关的神经元变化是依赖于年龄的细胞程序，损害了神经元特性。
