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 Zhou; Chen 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

doi:10.1016/j.neuron.2020.11.002

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

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109 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 language	English
Pages (from-to)	257-272.e14
Journal	Neuron
Volume	109
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2020.11.002
State	Published - 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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10.1016/j.neuron.2020.11.002

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Wang, M., Li, A., Sekiya, M., Beckmann, N. D., Quan, X., Schrode, N., Fernando, M. B., Yu, A., Zhu, L., Cao, J., Lyu, L., Horgusluoglu, E., Wang, Q., Guo, L., Wang, Y. S., Neff, R., Song, W. M., Wang, E., Shen, Q., ... Zhang, B. (2021). Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease. Neuron, 109(2), 257-272.e14. https://doi.org/10.1016/j.neuron.2020.11.002

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

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.",

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

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

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2021",

month = jan,

day = "20",

doi = "10.1016/j.neuron.2020.11.002",

language = "English",

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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 2021, 'Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease', Neuron, vol. 109, no. 2, pp. 257-272.e14. https://doi.org/10.1016/j.neuron.2020.11.002

TY - JOUR

T1 - Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease

AU - Wang, Minghui

AU - Li, Aiqun

AU - Sekiya, Michiko

AU - Beckmann, Noam D.

AU - Quan, Xiuming

AU - Schrode, Nadine

AU - Fernando, Michael B.

AU - Yu, Alex

AU - Zhu, Li

AU - Cao, Jiqing

AU - Lyu, Liwei

AU - Horgusluoglu, Emrin

AU - Wang, Qian

AU - Guo, Lei

AU - Wang, Yuan shuo

AU - Neff, Ryan

AU - Song, Won min

AU - Wang, Erming

AU - Shen, Qi

AU - Zhou, Xianxiao

AU - Ming, Chen

AU - Ho, Seok Man

AU - Vatansever, Sezen

AU - Kaniskan, H. Ümit

AU - Jin, Jian

AU - Zhou, Ming Ming

AU - Ando, Kanae

AU - Ho, Lap

AU - Slesinger, Paul A.

AU - Yue, Zhenyu

AU - Zhu, Jun

AU - Katsel, Pavel

AU - Gandy, Sam

AU - Ehrlich, Michelle E.

AU - Fossati, Valentina

AU - Noggle, Scott

AU - Cai, Dongming

AU - Haroutunian, Vahram

AU - Iijima, Koichi M.

AU - Schadt, Eric

AU - Brennand, Kristen J.

AU - Zhang, Bin

PY - 2021/1/20

Y1 - 2021/1/20

N2 - 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.

AB - 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.

KW - ATP6V1A

KW - Alzheimer's disease

KW - Drosophila

KW - NCH-51

KW - NGN2 neurons

KW - human induced pluripotent stem cell

KW - network biology

KW - neuronal dysregulation

KW - omics

UR - http://www.scopus.com/inward/record.url?scp=85097478119&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2020.11.002

DO - 10.1016/j.neuron.2020.11.002

M3 - Article

C2 - 33238137

AN - SCOPUS:85097478119

SN - 0896-6273

VL - 109

SP - 257-272.e14

JO - Neuron

JF - Neuron

IS - 2

ER -

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

Abstract

Keywords

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