The TREM2 R47H variant is associated with liver-plasma-brain axis dyshomeostasis in the 5xFAD mouse model of Alzheimer's disease.

The human Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene is expressed predominantly by microglia in the brain and the R47H coding variant of TREM2 is associated with increased risk for late-onset Alzheimer's disease (LOAD). We performed lipidomic and metabolomic analysis of liver, plasma, and brain in 4- and 12-month-old Trem2R47H homozygous (n = 27), 5xFAD hemizygous (n = 63), 5xFAD hemizygous, Trem2R47H homozygous (n = 25), and wild type (n = 65) mice. Lipid and metabolite abundances differed significantly across tissue types with the most differences seen in the liver and plasma of Trem2R47H mice at the 4-month timepoint. Cross-tissue correlation analyses revealed increased metabolic crosstalk along the liver-plasma-brain axis in Trem2R47H mice. Plasma triacylglyceride levels were significantly lower in females compared to males regardless of genotype, and 5-methyltetrahydrofolic acid levels were elevated in the brains of animals homozygous for the Trem2R47H variant. Together, these findings demonstrate early dyshomeostasis of the liver-plasma-brain axis of Trem2R47H mice which impacts several key metabolic pathways involving lipids, cellular energy metabolism, and brain folate metabolism.