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

Abstract

BackgroundOligodendrocytes (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.MethodsIn 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.ResultsThe 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0219-3) contains supplementary material, which is available to authorized users.

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation

“…A previous study investigating the relationship of a similar myelin/oligodendrocyte mRNA brain co-expression module to AD found that expression of this module decreased in both AD and PSP in temporal cortex, with stronger changes in PSP 76 . Another mRNA network study observed downregulation of oligodendrocyte module hubs in AD 77 . We observed an increase in this module in AD, with no changes in PSP.…”

“…The discrepancy in our findings may relate to possible differences between DLPFC and temporal cortex in this co-expression module, differences in module membership that may be important for disease relationship, or a divergence between mRNA and protein expression in M2 module members. In fact, the basis for disease causality regarding the M2 myelin/oligodendrocyte module may relate more to dysregulation of module member co-expression, rather than to the actual change in direction of expression 77 .…”

“…Following regression of each individual cohort, we assessed whether any cohort-specific tissue dissection bias was present by performing a Spearman rank correlation of traits including age, sex, PMI, and white matter markers to the top five principle components (PC) of log 2 (abundance). Network outlier case samples were not considered in the PCs, and were identified prior to PC analysis using Oldham's 'SampleNetworks' v1.06 R script 12 as previously published 136 using a 3 fold-SD cutoff of Z-transformed sample connectivity. The Spearman rank correlation was performed prior to correction of cohort-specific batch effects as described above, and after intra-cohort batch correction of the MSSB and Banner cohorts.…”

“…We used the WeiGhted Correlation Network Analysis (WGCNA) algorithm for our network analysis pipeline, as previously described 77 . A weighted protein co-expression network for the four-cohort consensus data was generated using the 3,334 log 2 protein abundance x 419 case-sample matrix that had undergone covariate and batch correction as described above.…”

“…To characterize differentially expressed proteins and co-expressed proteins based on gene ontology annotation, we used GO Elite v1.2.5 as previously published 77 , with pruned output visualized using an in-house R script. Cell type enrichment was also investigated as previously published 77 . Astrocyte subtype markers were obtained from Zamanian et al 43 .…”