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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Loss-of-function variants in the *TREM2* gene are linked to late-onset Alzheimer's disease (LOAD).
• Assessing the R47H missense variant and its impact on TREM2 expression is crucial for understanding LOAD.
• Developing accurate preclinical models is essential for studying TREM2's role in Alzheimer's.

Purpose of the Study:

• To molecularly characterize two mouse models of *TREM2* variants associated with LOAD.
• To compare the molecular signatures of these models with human LOAD brain expression data.
• To evaluate the utility of these models for investigating LOAD pathogenesis.

Main Methods:

• Humanization of the aberrant splice acceptor site in the Trem2*R47H mouse model to create the Trem2*R47H^HSS model.
• RNA sequencing of mouse brain tissue to analyze gene expression signatures.
• Comparison of mouse expression signatures with human postmortem brain expression data from LOAD cohorts.

Main Results:

• Trem2*R47H mice exhibited alternative splicing, reducing *Trem2* expression, while Trem2*R47H^HSS mice showed wild-type *Trem2* transcript and protein levels.
• Both models displayed LOAD-associated signatures and impacted immune response, synapse, and vasculature biodomains.
• The Trem2*R47H model additionally influenced extracellular matrix and myelination signatures.

Conclusions:

• Trem2*R47H and Trem2*R47H^HSS mice serve as valuable and complementary models for LOAD research.
• These models facilitate the study of the molecular mechanisms underlying LOAD pathology.
• Further investigation using these models can elucidate TREM2's contribution to Alzheimer's disease.