Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease
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Abstract
Genetic and genome-wide association studies suggest a central role for microglia in Alzheimer's disease (AD). However, single-cell RNA sequencing (scRNA-seq) of microglia in mice, a key preclinical model, has shown mixed results regarding translatability to human studies. To address this, scRNA-seq of microglia from C57BL/6J (B6) and wild-derived strains (WSB/EiJ, CAST/EiJ, and PWK/PhJ) with and without APP/PS1 demonstrates that genetic diversity significantly alters features and dynamics of microglia in baseline neuroimmune functions and in response to amyloidosis. Results show significant variation in the abundance of microglial subtypes or states, including numbers of previously identified disease-associated and interferon-responding microglia, across the strains. For each subtype, significant differences in the expression of many genes are observed in wild-derived strains relative to B6, including 19 genes previously associated with human AD including Apoe, Trem2, and Sorl1. This resource is critical in the development of appropriately targeted therapeutics for AD and other neurological diseases.
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Transcriptomic data from Onos and colleagues showed a compelling effect of these three wild-derived strains on amyloid accumulation.
“Transcriptomic data from Onos and colleagues showed a compelling effect of these three wild-derived strains on amyloid accumulation (Onos et al., 2019; Yang et al., 2021).”
From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Yang et al., 2021
The Introduction and Results report transcriptomic differences among the wild-derived strains in microglial responses to amyloid. The Results also report higher cerebral amyloid angiopathy in WSB.APP/PS1, but the cited paper does not show that its transcriptomic data establish an effect of all three strains on amyloid accumulation. Page numbers were not supplied in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredResponses of homeostatic microglia and disease-associated microglia are determined by wild-derived genetic backgrounds.
“Single-cell RNA sequencing (RNA-seq) of sorted microglia further demonstrated that the responses of immune cell subtypes, namely homeostatic microglia and disease-associated microglia (DAMs), are determined by wild-derived genetic backgrounds (Yang et al., 2021).”
From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Yang et al., 2021
Recent studies in AD have shown that mouse genetic background can modulate Aβ accumulation, immune response, and tau propagation.
“Recent studies in AD have shown that mouse genetic background can modulate Aβ accumulation (Onos et al., 2019), immune response (Yang et al., 2021), and tau propagation (Dujardin et al., 2022).”
From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Yang et al., 2021
Previous studies of Trem2 on mixed background mice indicated an allele inherited by the SJL strain that unknowingly introduced a missense mutation.
“Previous studies of Trem2 on mixed background mice indicated an allele inherited by the SJL strain that unknowingly introduced a missense mutation (Yang et al., 2021).”
From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Yang et al., 2021
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“Single-cell RNA sequencing (RNA-seq) of sorted microglia further demonstrated that the responses of immune cell subtypes, namely homeostatic microglia and disease-associated microglia (DAMs), are determined by wild-derived genetic backgrounds (Yang et al., 2021).”
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Self-citation
- Authors
- Yang, H. S., Onos, K. D., Choi, K., Keezer, K. J., Skelly, D. A., Carter, G. W., & Howell, G. R.
- Affiliations
- Jackson Laboratory (US)
- Tufts University (US)
- Corresponding author
- Howell, Gareth R.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 34
- Issue
- 6
- Pages
- 108739
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7937391
- OpenAlex
- W3128058731
- Cited by
- 69
- References
- 64
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 16 · 2023: 14 · 2022: 15 · 2021: 9
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- SSRN Electronic Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (RF1AG051496, RF1AG055104)
- Alzheimer's Association (2018-AARF-589154)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- Alzheimer's disease, natural genetic variation, wild-derived mouse strains, APP/PS1 mice, microglial subtypes, disease-associated microglia, amyloidosis, neuroinflammation, apolipoprotein E, TREM2, SORL1, C57BL/6J mice, CAST/EiJ
- MeSH terms
- RNA-Seq, Alzheimer Disease, Animals, Disease Models, Animal, Species Specificity, Genetic Variation, Microglia, Mice, Genome-Wide Association Study
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