Opposite microglial activation stages upon loss of PGRN result in reduced cerebral glucose metabolism

Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD). Among these genes are progranulin (GRN) and the triggering receptor expressed on myeloid cells 2 (TREM2). Both cause neurodegeneration by mechanisms involving loss-of-function. We have now isolated microglia from Grn–/– mice and compared their transcriptomes to those of Trem2–/– mice. Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn–/– mice showed a reciprocal activation of the MGnD molecular signature and suppression of genes characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro-2-deoxy-D-glucose)-µPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction. In this study we analyzed microglial gene expression in total RNA from acutely isolated microglia of brain from adult mice. We compared the expression profile of Grn knockout mice (n=5, 5.5 months, male) to wildtype mice (n=5, 5.5 months, male).