Abstract
INTRODUCTION: The R47H missense mutation of the TREM2 gene is a strong risk factor for development of Alzheimer's Disease. We investigate cell-type-specific spatial transcriptomic changes induced by the Trem2(R47H) mutation to determine the impacts of this mutation on transcriptional dysregulation. METHODS: We profiled 15 mouse brain sections consisting of wild-type, Trem2(R47H), 5xFAD and Trem2(R47H); 5xFAD genotypes using MERFISH spatial transcriptomics. Single-cell spatial transcriptomics and neuropathology data were analyzed using our custom pipeline to identify plaque and Trem2(R47H) induced transcriptomic dysregulation. RESULTS: The Trem2(R47H) mutation induced consistent upregulation of Bdnf and Ntrk2 across many cortical excitatory neuron types, independent of amyloid pathology. Spatial investigation of genotype enriched subclusters identified spatially localized neuronal subpopulations reduced in 5xFAD and Trem2(R47H); 5xFAD mice. CONCLUSION: Spatial transcriptomics analysis identifies glial and neuronal transcriptomic alterations induced independently by 5xFAD and Trem2(R47H) mutations, impacting inflammatory responses in microglia and astrocytes, and activity and BDNF signaling in neurons.