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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BMC
2017-11-01
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Series: | Molecular Neurodegeneration |
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Online Access: | http://link.springer.com/article/10.1186/s13024-017-0219-3 |
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doaj-8d4fe7e565604e8b95a879118cca0dc9 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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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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 |