[O2–13–06]: ASSESSING TREM2 FUNCTION IN ALZHEIMER's DISEASE WITH RNA‐SEQ

Rare heterozygous variants in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene are associated with increased susceptibility to late-onset Alzheimer's disease (LOAD), with the R47H allele having a comparable odds ratio (∼3) to the ε4 allele of apolipoprotein E. TREM2 forms a receptor signalling complex with TYROBP and triggers activation of the immune responses in macrophages, dendritic cells and microglia. Previous reports have described an immune- and microglia-gene enriched mRNA co-expression network centred on TYROBP and TREM2 that is perturbed in AD brain, providing evidence of a general role for TREM2 in LOAD. Our work builds on these expression-array based studies by investigating the effects of expression changes in brain tissue from TREM2 KO mice and brain tissue samples human carriers of TREM2 pathogenic mutations using RNA-seq, which will shed light on the role of TREM2 in AD pathogenesis. We used RNA-Seq on brain tissue using human samples with rare TREM2 risk variants, and on TREM2 KO mice brain samples analysed at 4 and 8 months of age. Differential expression analysis of the TREM2 KO mice gene RNAseq data revealed that most of the differences between knockout and wild type mice occurred at 4 months of age. The functional features of co-expressed genes modules particularly sensitive to an absence of TREM2, age and tissue were investigated further. We found that some of the largest disruptions occurred in a module that is enriched with genes highly expressed in endothelial cells. The key goal of our project is to gain an understanding of TREM2 pathways relevant to AD vulnerability in order to identify the underlying biological processes relevant to pathophysiology. We will achieve this goal using transcriptome RNA-Seq data on both human brain samples harbouring the rare TREM2 risk variant and mouse model systems to evaluate these models as a tool for treatment development. Our early results suggest that endothelial cells may be vulnerable to the effects of the loss of TREM2 expression.