Lack of TREM2 differentially affects the phenotype and transcriptome of mice expressing human APOE3 and APOE4

We aim to investigate the interaction between two of the major genetic risk factors for AD: inheritance of APOEe4 and deficiency of Triggering Receptor Expressed on Myeloid cells 2 (TREM2). Trem2 deletion worsened memory in AD model mice but not in their WT littermates. Interestingly, the lack Trem2 resulted in a significantly less microglia around amyloid plaques in APP mice expressing both APOE isoforms but had no impact on amyloid load. Gene expression analysis identified as Trem2 signature a cluster of highly connected immune response genes, commonly downregulated as a result of Trem2 deletion in all experimental groups, such as Clec7a, Itgax, Cts7, Mpeg1, Csf1r, Cx3cr1, Pik3cg and Spi1/PU.1. In vitro experiments with primary microglia demonstrated a decrease of Aß phagocytosis in APOE4 versus APOE3 microglia a difference that was augmented by the absence of Trem2. Our data demonstrate that the lack of Trem2 differentially impact the phenotype and brain transcriptome of APP mice expressing human APOE isoforms probably reflecting the difference between APOE isoforms to transport lipids that can affect APOE receptor-binding properties. Overall design: We crossed 6.5 month old male and female Trem2ko mice with APP/PSEN1dE9 mice expressing human APOE3 or APOE4 isoforms and assessed amyloid pathology, glial response, and whole-brain transcriptome.