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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2017

Open Access 01-12-2017 | Research article

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

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

Published in: Molecular Neurodegeneration | Issue 1/2017

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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.
Appendix
Available only for authorised users
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Metadata
Title
Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease
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
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2017
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-017-0219-3

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Molecular Neurodegeneration 1/2017 Go to the issue

Methodology

Separation of photoreceptor cell compartments in mouse retina for protein analysis

Commentary

Diurnal oscillation of CSF Aβ and other AD biomarkers

Research article

GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord

Research article

Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring

Research article

A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway

Review

NADPH oxidases in Parkinson’s disease: a systematic review