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Mol Neurodegener. 2017 Nov 6;12(1):82. doi: 10.1186/s13024-017-0219-3.

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

McKenzie AT1,2,3, Moyon S4,5, Wang M1,2, Katsyv I1,2,3, Song WM1,2, Zhou X1,2, Dammer EB6, Duong DM7,8, Aaker J9, Zhao Y1,2, Beckmann N1,2, Wang P1,2, Zhu J1,2, Lah JJ10,11, Seyfried NT7,8,10, Levey AI10,11, Katsel P12, Haroutunian V2,12,13, Schadt EE1,2, Popko B9, Casaccia P14,15,16, Zhang B17,18.

Author information

1
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, 1470 Madison Avenue, Room S8-111, New York, NY, 10029, USA.
2
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
3
Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
4
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
5
Neuroscience Initiative, The City University of New York, Advanced Science Research Center, 85 St. Nicholas Terrace, New York, NY, 10031, USA.
6
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
7
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA.
8
Integrated Proteomics Core Facility, Emory University School of Medicine, Atlanta, GA, 30322, USA.
9
Department of Neurology, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA.
10
Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
11
Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, 30322, USA.
12
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
13
Mental Illness Research, Education, and Clinical Center (VISN 3), James J. Peters VA Medical Center, Bronx, NY, 10468, USA.
14
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. Patrizia.Casaccia@mssm.edu.
15
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. Patrizia.Casaccia@mssm.edu.
16
Neuroscience Initiative, The City University of New York, Advanced Science Research Center, 85 St. Nicholas Terrace, New York, NY, 10031, USA. Patrizia.Casaccia@mssm.edu.
17
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, 1470 Madison Avenue, Room S8-111, New York, NY, 10029, USA. bin.zhang@mssm.edu.
18
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. bin.zhang@mssm.edu.

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.

KEYWORDS:

Alzheimer’s disease; BIN1; CNP; Causal network; Differential expression; Myelin; Oligodendrocyte; Proteomics; RNA sequencing; co-expression network

PMID:
29110684
PMCID:
PMC5674813
DOI:
10.1186/s13024-017-0219-3
[Indexed for MEDLINE]
Free PMC Article

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