Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease

Minghui Wang, Aiqun Li, Michiko Sekiya, Noam D. Beckmann, Xiuming Quan, Nadine Schrode, Michael B. Fernando, Alex Yu, Li Zhu, Jiqing Cao, Liwei Lyu, Emrin Horgusluoglu, Qian Wang, Lei Guo, Yuan shuo Wang, Ryan Neff, Won min Song, Erming Wang, Qi Shen, Xianxiao ZhouChen Ming, Seok Man Ho, Sezen Vatansever, H. Ümit Kaniskan, Jian Jin, Ming Ming Zhou, Kanae Ando, Lap Ho, Paul A. Slesinger, Zhenyu Yue, Jun Zhu, Pavel Katsel, Sam Gandy, Michelle E. Ehrlich, Valentina Fossati, Scott Noggle, Dongming Cai, Vahram Haroutunian, Koichi M. Iijima, Eric Schadt, Kristen J. Brennand, Bin Zhang

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)257-272.e14
JournalNeuron
Volume109
Issue number2
DOIs
StatePublished - 20 Jan 2021

Keywords

  • ATP6V1A
  • Alzheimer's disease
  • Drosophila
  • NCH-51
  • NGN2 neurons
  • human induced pluripotent stem cell
  • network biology
  • neuronal dysregulation
  • omics

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