Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease
Open accessAbstract
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.
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RNA sequencing of human postmortem brain tissue reinforces the importance of microglial and inflammatory mechanisms in AD pathogenesis, among other pathways.
“Results from RNA sequencing (RNA-seq) of human postmortem brain tissue further reinforce the importance of microglial and inflammatory mechanisms in AD pathogenesis, among other pathways (Allen et al., 2018; Conway et al., 2018; McKenzie et al., 2017; Patrick et al., 2017; Wang et al., 2016, 2019; Zhang et al., 2013).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as McKenzie et al., 2017
The Discussion (page unavailable) reports that a co-expression module derived from human postmortem AD brains was enriched for immune and microglial genes, supporting the claim’s biological point alongside other pathways. But the Methods describe RNA-seq for mouse knockout experiments, not for the human postmortem analysis; they do not support calling the human result an RNA-seq finding. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGene sets from prior AD-associated oligodendrocyte-enriched coexpression modules significantly overlapped with consensus cluster D.
“independent analyses of RNA-seq from the Mayo and MSSM cohorts previously identified AD-associated coexpression modules enriched for oligodendrocyte expression signatures (Allen et al., 2018; McKenzie et al., 2017), and these gene sets significantly overlapped with consensus cluster D (Figure 1C).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as McKenzie et al., 2017
A recent large-scale transcriptomic network analysis in the human AD brain demonstrated significant enrichment of AD GWAS candidates in conserved disease-associated oligodendrocyte-enriched modules, including BIN1, PICALM, and several others.
“a recent large-scale transcriptomic network analysis in the human AD brain (DLPFC, visual cortex, cerebellum), which demonstrated significant enrichment of AD GWAS candidates in conserved disease-associated oligodendrocyte-enriched modules, including BIN1, PICALM, and several others [130].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [130]
At least 50% overlap was found between oligodendrocyte modules of a transcriptome network and an independently constructed proteomic network from AD brain tissue.
“the authors found at least 50% overlap between oligodendrocyte modules of the two datasets.”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [130]
Recent transcriptomic data suggest alterations in oligodendrocyte and myelination biology in AD brain.
“which is consistent with recent transcriptomic data suggesting alterations in oligodendrocyte and myelination biology in AD brain [30, 47].”
From Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease (2018) · cites this paper as [47]
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References 96 · Cited by 154
Research works printed but not linked: 1
- [84]Miller JA Woltjer RL Goodenbour JM Horvath S Geschwind DH Genes and pathways underlying regional and cell type changes in Alzheimer’s disease Genome Med 2013 5 48 10.1186/gm452 23705665 PMC3706780 · DOI · Paper page
- Authors
- McKenzie, A. T., Moyon, S., Wang, M., Katsyv, I., Song, W.-M., Zhou, X., Dammer, E. B., Duong, D. M., Aaker, J., Zhao, Y., Beckmann, N., Wang, P., Zhu, J., Lah, J. J., Seyfried, N. T., Levey, A. I., Katsel, P., Haroutunian, V., Schadt, E. E., Popko, B., Casaccia, P., & Zhang, B.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- City University of New York (US)
- Emory University (US)
- University of Chicago (US)
- New York/New Jersey VA Health Care Network (US)
- Corresponding author
- Casaccia, Patrizia
- Zhang, Bin
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2017-11-06
- Volume
- 12
- Issue
- 1
- Pages
- 82-82
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC5674813
- OpenAlex
- W2767972214
- Cited by
- 154
- References
- 96
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 11 · 2023: 16 · 2022: 28 · 2021: 36 · 2020: 20 · 2019: 10 · 2018: 7
- FWCI
- 7.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (R01AG046170, U01AI111598, P50 AG025688, U01AG046161, F30AG052261, RF1AG054014, R01NS067550)
- National Institute on Aging (RF1AG057440, R01AG057907)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- oligodendrocytes, Alzheimer's disease, gene co-expression network, dysmyelination, BIN1, UGT8, CNP, PLP1, GOT2, mitochondrial gene expression, postmortem brain
- MeSH terms
- Alzheimer Disease, Animals, Humans, Models, Neurological, Myelin Sheath, Oligodendroglia, Gene Expression Profiling, Mice, Gene Regulatory Networks
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