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

33238137
PMC7855384
Neuron
Jan. 20, 2021
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. Electronic address: bin.zhang@mssm.edu.
Databases, Genetic, Drosophila melanogaster, Gene Regulatory Networks, Animals, Genetically Modified, Signal Transduction, Induced Pluripotent Stem Cells, Sequence Analysis, RNA, Alzheimer Disease, Brain, Animals, Male, Female, Humans
R01 DA043247, R01 DK118243, U01 AI111598, R03 DE026814, R01 MH121074, U01 AG058635, RF1 AG059319, R01 AG068030, R01 AG062355, U01 AG052411, R01 AG057907, RF1 AG057440, RF1 AG054014, U01 AG046170
Yue Z, Iijima KM, Slesinger PA, Kaniskan HÜ, Wang YS, Yu A, Horgusluoglu E, Ho SM, Quan X, Zhou MM, Sekiya M, Ando K, Schrode N, Lyu L, Fernando MB, Neff R, Shen Q, Zhou X, Li A, Vatansever S, Ho L, Fossati V, Noggle S, Song WM, Wang Q, Wang E, Ming C, Beckmann ND, Ehrlich ME, Cao J, Zhu L, Cai D, Guo L, Jin J, Wang M, Schadt E, Katsel P, Gandy S, Brennand KJ, Zhu J, Zhang B, Haroutunian V
Wang M, Li A, Sekiya M, Beckmann ND, Quan X, Schrode N, Fernando MB, Yu A, Zhu L, Cao J, Lyu L, Horgusluoglu E, Wang Q, Guo L, Wang YS, Neff R, Song WM, Wang E, Shen Q, Zhou X, Ming C, Ho SM, Vatansever S, Kaniskan HÜ, Jin J, Zhou MM, Ando K, Ho L, Slesinger PA, Yue Z, Zhu J, Katsel P, Gandy S, Ehrlich ME, Fossati V, Noggle S, Cai D, Haroutunian V, Iijima KM, Schadt E, Brennand KJ, Zhang B. Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease. Neuron 2021 Jan 20.

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.