Trem2*R47H and reduced TREM2 expression both mimic human Alzheimer's disease signatures in mice

Abel, T. R.; Pandey, R. S.; Haber, A.; Garceau, D.; Sasner, M. J.; Kotredes, K. P.; Cary, G. A.; Oblak, A.; Howell, G. R.; Lamb, B. T.; Carter, G. W.

doi:10.64898/2025.12.17.694758

bioRxiv · 10.64898/2025.12.17.694758

Trem2*R47H and reduced TREM2 expression both mimic human Alzheimer's disease signatures in mice

Abel, T. R.·Pandey, R. S.·Haber, A.·Garceau, D.·Sasner, M. J.·Kotredes, K. P.·Cary, G. A.·Oblak, A.·Howell, G. R.·Lamb, B. T.·Carter, G. W.

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Abstract

INTRODUCTIONTREM2 loss of function variants are associated with late-onset Alzheimers disease (LOAD). We molecularly assessed mice with the missense variant, R47H (Trem2*R47HHSS), and mice with additional cryptic splicing and reduced Trem2 expression (Trem2*R47H) while comparing relevance to human LOAD. METHODSThe aberrant splice acceptor site in the Trem2*R47H mouse was humanized resulting in the Trem2*R47H humanized splice site (Trem2*R47HHSS) mouse. RNA sequencing was performed on mouse brain tissue and signatures were compared to human postmortem brain expression in LOAD cohorts. RESULTSTrem2*R47H mice had alternative splicing leading to reduced Trem2 expression; Trem2*R47HHSS mice expressed Trem2 at wild-type transcript and protein levels. Both models correlated with similar LOAD-associated signatures, and had similar effects on immune response, synapse, and vasculature biodomains. The Trem2*R47H model additionally affected extracellular matrix and myelination signatures. DISCUSSIONWe demonstrated that Trem2*R47H and Trem2*R47HHSS mice are complementary models for the study of molecular contributions to LOAD pathology.

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Abel, T. R., Pandey, R. S., Haber, A., Garceau, D., Sasner, M. J., Kotredes, K. P., Cary, G. A., Oblak, A., Howell, G. R., Lamb, B. T., Carter, G. W.. 2025-12-19. Trem2*R47H and reduced TREM2 expression both mimic human Alzheimer's disease signatures in mice. https://doi.org/10.64898/2025.12.17.694758

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