Trem2R47H and reduced TREM2 expression both mimic human Alzheimer's disease signatures in mice.

INTRODUCTION: TREM2 loss of function variants are associated with late-onset Alzheimer's 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. METHODS: The 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. RESULTS: Trem2*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. DISCUSSION: We demonstrated that Trem2*R47H and Trem2*R47HHSS mice are complementary models for the study of molecular contributions to LOAD pathology.