Assembly and Interrogation of Alzheimer’s Disease Genetic Networks Reveal Novel Regulators of Progression
Open accessAbstract
Alzheimer's disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression.
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The expression and activity of p300 are increased in the brain of AD patients, and dysregulation of p300/CBP promotes tau acetylation, which could aggravate tau accumulation and pathology.
“The expression and activity of p300 are increased in the brain of AD patients [179], and the dysregulation of p300/CBP promotes tau acetylation, which could aggravate tau accumulation and pathology [46, 48].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [179]
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References 63 · Cited by 106
- Authors
- Aubry, S., Shin, W., Crary, J. F., Lefort, R., Qureshi, Y. H., Lefebvre, C., Califano, A., & Shelanski, M. L.
- Affiliations
- Columbia University (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Califano, Andrea
- Shelanski, Michael L.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-03-17
- Volume
- 10
- Issue
- 3
- Pages
- e0120352
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4363671
- OpenAlex
- W2092010840
- Cited by
- 106
- References
- 63
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 3 · 2023: 11 · 2022: 9 · 2021: 13 · 2020: 14 · 2019: 12 · 2018: 11 · 2017: 6 · 2016: 7 · 2015: 10
- FWCI
- 8.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Columbia Academic Commons (Columbia University)
- Funders
- Alzheimer's Association (NIRG-11-204450)
- National Institutes of Health (CA121852, U54-CA121852)
- National Institute on Aging (P30AG036453)
- National Cancer Institute (U54CA121852)
- National Institute of General Medical Sciences (T32GM008798)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- Alzheimer's disease, disease progression, transcriptional regulatory networks, master regulators, transcription factor-target interactions, neuronal gene expression, ARACNE, marinas, YY1, P300, p53, neurodegeneration, systems biology
- MeSH terms
- Alzheimer Disease, Animals, Gene Expression Regulation, Humans, Nerve Tissue Proteins, Rats, Gene Regulatory Networks
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