Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease

Abstract Background Oligodendrocytes (OLs) and myelin are critical for normal brain function and have been implicated in neurodegeneration. Several lines of evidence including neuroimaging and neuropathological data suggest that Alzheimer’s disease (AD) may be associated with dysmyelination and a br...

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Main Authors: Andrew T. McKenzie, Sarah Moyon, Minghui Wang, Igor Katsyv, Won-Min Song, Xianxiao Zhou, Eric B. Dammer, Duc M. Duong, Joshua Aaker, Yongzhong Zhao, Noam Beckmann, Pei Wang, Jun Zhu, James J. Lah, Nicholas T. Seyfried, Allan I. Levey, Pavel Katsel, Vahram Haroutunian, Eric E. Schadt, Brian Popko, Patrizia Casaccia, Bin Zhang
Format: Article
Language:English
Published: BMC 2017-11-01
Series:Molecular Neurodegeneration
Subjects:
Online Access:http://link.springer.com/article/10.1186/s13024-017-0219-3
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author Andrew T. McKenzie
Sarah Moyon
Minghui Wang
Igor Katsyv
Won-Min Song
Xianxiao Zhou
Eric B. Dammer
Duc M. Duong
Joshua Aaker
Yongzhong Zhao
Noam Beckmann
Pei Wang
Jun Zhu
James J. Lah
Nicholas T. Seyfried
Allan I. Levey
Pavel Katsel
Vahram Haroutunian
Eric E. Schadt
Brian Popko
Patrizia Casaccia
Bin Zhang
spellingShingle Andrew T. McKenzie
Sarah Moyon
Minghui Wang
Igor Katsyv
Won-Min Song
Xianxiao Zhou
Eric B. Dammer
Duc M. Duong
Joshua Aaker
Yongzhong Zhao
Noam Beckmann
Pei Wang
Jun Zhu
James J. Lah
Nicholas T. Seyfried
Allan I. Levey
Pavel Katsel
Vahram Haroutunian
Eric E. Schadt
Brian Popko
Patrizia Casaccia
Bin Zhang
Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease
Molecular Neurodegeneration
Alzheimer’s disease
Oligodendrocyte
Myelin
co-expression network
Causal network
RNA sequencing
author_facet Andrew T. McKenzie
Sarah Moyon
Minghui Wang
Igor Katsyv
Won-Min Song
Xianxiao Zhou
Eric B. Dammer
Duc M. Duong
Joshua Aaker
Yongzhong Zhao
Noam Beckmann
Pei Wang
Jun Zhu
James J. Lah
Nicholas T. Seyfried
Allan I. Levey
Pavel Katsel
Vahram Haroutunian
Eric E. Schadt
Brian Popko
Patrizia Casaccia
Bin Zhang
author_sort Andrew T. McKenzie
title Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease
title_short Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease
title_full Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease
title_fullStr Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease
title_full_unstemmed Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease
title_sort multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in alzheimer’s disease
publisher BMC
series Molecular Neurodegeneration
issn 1750-1326
publishDate 2017-11-01
description Abstract Background Oligodendrocytes (OLs) and myelin are critical for normal brain function and have been implicated in neurodegeneration. Several lines of evidence including neuroimaging and neuropathological data suggest that Alzheimer’s disease (AD) may be associated with dysmyelination and a breakdown of OL-axon communication. Methods In order to understand this phenomenon on a molecular level, we systematically interrogated OL-enriched gene networks constructed from large-scale genomic, transcriptomic and proteomic data obtained from human AD postmortem brain samples. We then validated these networks using gene expression datasets generated from mice with ablation of major gene expression nodes identified in our AD-dysregulated networks. Results The robust OL gene coexpression networks that we identified were highly enriched for genes associated with AD risk variants, such as BIN1 and demonstrated strong dysregulation in AD. We further corroborated the structure of the corresponding gene causal networks using datasets generated from the brain of mice with ablation of key network drivers, such as UGT8, CNP and PLP1, which were identified from human AD brain data. Further, we found that mice with genetic ablations of Cnp mimicked aspects of myelin and mitochondrial gene expression dysregulation seen in brain samples from patients with AD, including decreased protein expression of BIN1 and GOT2. Conclusions This study provides a molecular blueprint of the dysregulation of gene expression networks of OL in AD and identifies key OL- and myelination-related genes and networks that are highly associated with AD.
topic Alzheimer’s disease
Oligodendrocyte
Myelin
co-expression network
Causal network
RNA sequencing
url http://link.springer.com/article/10.1186/s13024-017-0219-3
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spelling doaj-8d4fe7e565604e8b95a879118cca0dc92020-11-24T23:56:12ZengBMCMolecular Neurodegeneration1750-13262017-11-0112112010.1186/s13024-017-0219-3Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s diseaseAndrew T. McKenzie0Sarah Moyon1Minghui Wang2Igor Katsyv3Won-Min Song4Xianxiao Zhou5Eric B. Dammer6Duc M. Duong7Joshua Aaker8Yongzhong Zhao9Noam Beckmann10Pei Wang11Jun Zhu12James J. Lah13Nicholas T. Seyfried14Allan I. Levey15Pavel Katsel16Vahram Haroutunian17Eric E. Schadt18Brian Popko19Patrizia Casaccia20Bin Zhang21Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiFishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Human Genetics, Emory University School of MedicineDepartment of Biochemistry, Emory University School of MedicineDepartment of Neurology, The University of Chicago Pritzker School of MedicineDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Neurology, Emory University School of MedicineDepartment of Biochemistry, Emory University School of MedicineDepartment of Neurology, Emory University School of MedicineDepartment of Psychiatry, Icahn School of Medicine at Mount SinaiIcahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Neurology, The University of Chicago Pritzker School of MedicineIcahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiAbstract Background Oligodendrocytes (OLs) and myelin are critical for normal brain function and have been implicated in neurodegeneration. Several lines of evidence including neuroimaging and neuropathological data suggest that Alzheimer’s disease (AD) may be associated with dysmyelination and a breakdown of OL-axon communication. Methods In order to understand this phenomenon on a molecular level, we systematically interrogated OL-enriched gene networks constructed from large-scale genomic, transcriptomic and proteomic data obtained from human AD postmortem brain samples. We then validated these networks using gene expression datasets generated from mice with ablation of major gene expression nodes identified in our AD-dysregulated networks. Results The robust OL gene coexpression networks that we identified were highly enriched for genes associated with AD risk variants, such as BIN1 and demonstrated strong dysregulation in AD. We further corroborated the structure of the corresponding gene causal networks using datasets generated from the brain of mice with ablation of key network drivers, such as UGT8, CNP and PLP1, which were identified from human AD brain data. Further, we found that mice with genetic ablations of Cnp mimicked aspects of myelin and mitochondrial gene expression dysregulation seen in brain samples from patients with AD, including decreased protein expression of BIN1 and GOT2. Conclusions This study provides a molecular blueprint of the dysregulation of gene expression networks of OL in AD and identifies key OL- and myelination-related genes and networks that are highly associated with AD.http://link.springer.com/article/10.1186/s13024-017-0219-3Alzheimer’s diseaseOligodendrocyteMyelinco-expression networkCausal networkRNA sequencing