Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal
Open accessAbstract
It is clear that innate immune system status is altered in numerous neurodegenerative diseases. Human genetic studies have demonstrated that triggering receptor expressed in myeloid cells 2 (TREM2) coding variants have a strong association with Alzheimer's disease (AD) and other neurodegenerative diseases. To more thoroughly understand the impact of TREM2 in vivo, we studied the behavioral and cognitive functions of wild-type (WT) and Trem2-/- (KO) mice during basal conditions and brain function in the context of innate immune stimulation with peripherally administered lipopolysaccharide (LPS). Early markers of neuroinflammation preceded Aif1 and Trem2 upregulation that occurred at later stages (24-48 h post-LPS). We performed a transcriptomic study of these cohorts and found numerous transcripts and pathways that were altered in Trem2-/- mice both at baseline and 48 h after LPS challenge. Importantly, our transcriptome analysis revealed that our Trem2-/- mouse line (Velocigene allele) results in exaggerated Treml1 upregulation. In contrast, aberrantly high Treml1 expression was absent in the Trem2 knockout line generated by the Colonna lab and the Jackson Labs CRISPR/Cas9 Trem2 knockout line. Notably, removal of the floxed neomycin selection cassette ameliorated aberrant Treml1 expression, validating the artifactual nature of Treml1 expression in the original Trem2-/- Velocigene line. Clearly further studies are needed to decipher whether the Treml1 transcriptional artifact is functionally meaningful, but our data indicate that caution is warranted when interpreting functional studies with this particular line. Additionally, our results indicate that other Velocigene alleles or targeting strategies with strong heterologous promoters need to carefully consider downstream genes.
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Several Trem2 KO mice show various - sometimes contradictory - phenotypes due to alterations of expression in other genes beyond Trem2 (e.g. Trem1L) in some models.
“several Trem2 KO mice show various – sometimes contradictory – phenotypes due to alterations of expression in other genes beyond Trem2 (e.g. Trem1L) in some models [107]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [107]
The Results section ('Trem2 deletion alters Treml1 expression depending on targeting construct'; page unavailable) shows that Trem2 knockout strategies differ in their effects on Treml1 and other gene expression. But the Discussion says it is uncertain whether Treml1 compensates for or masks TREM2 deficiency; the paper does not establish that altered expression causes the differing or contradictory phenotypes claimed. (LLM, conf=0.88)
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“Interestingly, TREML1 levels in the brain have recently been associated with decreased AD risk in humans (59), suggesting that upregulated expression may be protective in disease.”
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Additional file 7 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160927
Additional file 6 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160924
Additional file 5 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160921
Additional file 8 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160930
Additional file 1 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160909
Additional file 4 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160918
Additional file 10 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160897
Additional file 11 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160900
Additional file 3 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160915
Additional file 2 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160912
Additional file 9 of Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Jadhav, V., Lin, P. B., Pennington, T., Prisco, G. V. D., Jannu, A. J., Xu, G., Moutinho, M., Zhang, J., Atwood, B. K., Puntambekar, S. S., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13160933
Vautheny, A. (2019) · theses.fr (ABES) · doi:10.70675/1812d71aze8d9z48d6z87d1z5a23a4e81953
TREM2-Targeting peptide tracer for neuroinflammation PET imaging
Zhang, X., Liu, W., Guo, N., Gao, X., Pu, S., Yang, Y., Zha, X., Ding, K., Shi, D., Zhao, J., et al. (2026) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-026-07929-9
- Authors
- Kang, S. S., Kurti, A., Baker, K. E., Liu, C.-C., Colonna, M., Ulrich, J. D., Holtzman, D. M., Bu, G., & Fryer, J. D.
- Affiliations
- Mayo Clinic (US)
- Washington University in St. Louis (US)
- Corresponding author
- Fryer, John D
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-10-11
- Volume
- 27
- Issue
- 2
- Pages
- 211-223
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC5886290
- OpenAlex
- W2762857072
- Cited by
- 62
- References
- 64
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 19 · 2019: 4 · 2018: 9 · 2017: 1
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Human Molecular Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- NIH (NS094137, AG047327, AG049992, MH103632, AG027924, AG035355, and NS074969)
- Mayo Foundation
- 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 › Inflammasome and immune disorders
- Keywords
- TREM2, TREM2 knockout mice, neuroinflammation, lipopolysaccharide challenge, innate immunity, Alzheimer's disease, neurodegenerative diseases, transcriptome, heterologous promoters
- MeSH terms
- Animals, Behavior, Animal, Brain, Cognition, Disease Models, Animal, Immunity, Innate, Membrane Glycoproteins, Mice, Inbred C57BL, Receptors, Immunologic, Up-Regulation, Microglia, Mice, Knockout, Gene Expression Profiling, Mice, Transcriptome
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