Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Neuron. 2021 Jan 20;109(2):257-272.e14. doi: 10.1016/j.neuron.2020.11.002. Epub 2020 Nov 24.
To identify the molecular mechanisms and novel therapeutic targets of late-onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of multi-omics profiling of four cortical areas across 364 donors with varying cognitive and neuropathological phenotypes. Our analyses revealed thousands of molecular changes and uncovered neuronal gene subnetworks as the most dysregulated in LOAD. ATP6V1A was identified as a key regulator of a top-ranked neuronal subnetwork, and its role in disease-related processes was evaluated through CRISPR-based manipulation in human induced pluripotent stem cell-derived neurons and RNAi-based knockdown in Drosophila models. Neuronal impairment and neurodegeneration caused by ATP6V1A deficit were improved by a repositioned compound, NCH-51. This study provides not only a global landscape but also detailed signaling circuits of complex molecular interactions in key brain regions affected by LOAD, and the resulting network models will serve as a blueprint for developing next-generation therapeutic agents against LOAD.
为了确定晚发性阿尔茨海默病（LOAD）的分子机制和新的治疗靶点，我们对 364 名具有不同认知和神经病理学表型的供体的四个皮质区域的多组学特征进行了综合网络分析。我们的分析揭示了数千个分子变化，并发现神经元基因子网络在 LOAD 中失调最严重。ATP6V1A 被确定为排名最高的神经元子网络的关键调节因子，通过在人类诱导多能干细胞衍生神经元中的 CRISPR 为基础的操作和在果蝇模型中的 RNAi 为基础的敲低来评估其在疾病相关过程中的作用。ATP6V1A 缺陷引起的神经元损伤和神经退行性变可以通过一种再定位的化合物 NCH-51 得到改善。这项研究不仅提供了一个全局景观，还详细描述了受 LOAD 影响的关键大脑区域中复杂分子相互作用的信号通路，所得的网络模型将作为开发针对 LOAD 的下一代治疗药物的蓝图。
