Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models
Abstract
Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial functi…
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Other studies have questioned the overall degree of conservation between AD mouse models and human brains.
“Although some studies have identified selected overlaps in expression changes between AD mouse models and human brains (Bennett et al., 2018; Castillo et al., 2017; Mostafavi et al., 2018; Neuner et al., 2019; Rojo et al., 2017), other studies have questioned the overall degree of conservation (Burns et al., 2015; Galatro et al., 2017; Hargis and Blalock, 2017).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Burns et al., 2015
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- Authors
- Burns, T. C., Li, M. D., Mehta, S., Awad, A. J., & Morgan, A. A.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Burns, Terry C.
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 759
- Pages
- 101-117
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W2030532945
- Cited by
- 79
- References
- 9
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 5 · 2021: 5 · 2020: 11 · 2019: 4 · 2018: 4 · 2017: 8 · 2016: 5 · 2015: 5
- FWCI
- 5.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- California Institute of Regenerative Medicine TG2-01159 (TCB)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- neurodegenerative diseases, mouse model, transcriptome, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, human-mouse comparison, aging, stress response genes, prion disease, translational research, clinical trial failure, mitochondrial function, DNA repair, chromatin maintenance
- MeSH terms
- Aging, Animals, Disease Models, Animal, Humans, Species Specificity, Computational Biology, Neurodegenerative Diseases, Animals, Genetically Modified, Mice, Translational Research, Biomedical, Transcriptome
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