Opposite microglial phenotypes upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism

Ziel/Aim:

Genes variants such as loss-of-function in the progranulin (GRN) or TREM2 gene are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) or Frontotemporal lobar degeneration (FTLD). Therefore, we aimed to investigate in the differences of microglial function and gene expression in a mouse model with GRN or TREM2 mutation.

Methodik/Methods:

GRN mice (n = 6), TREM2 mice (n = 8), and wild-type mice (WT, n = 10) aged between 8 and 11 months received dual small animal PET with F-18-GE180 and F-18-FDG to measure microglial activity and cerebral glucose metabolism. Values deriving from a neocortical target VOI were extracted and compared between groups of different genotypes. Microglia was isolated from mouse brains of 5.5 mo old GRN (n = 5) and WT (n = 5) mice. mRNA samples were used for gene expressing profiling.

Ergebnisse/Results:

TSPO-PET and mRNA expression profiles showed completely divergent functional microglia phenotypes in GRN compared to TREM2 loss-of-function mice. TREM2 microglia exhibited a TSPO decrease (-10% vs. WT), whereas GRN microglia showed a dramatically TSPO increase (+14% vs. WT). Although loss of TREM2 and progranulin function showed completely opposite microglial phenotypes, F-18-FDG-PET revealed significantly reduced glucose metabolism in both conditions (-14 and -19% vs. WT).

Schlussfolgerungen/Conclusions:

Opposite microglial phenotypes result in similar brain dysfunction. Arresting microglia in any of the two extreme states is detrimental, causes similar neurological consequences and result in neurodegenerative diseases. Therefore, the therapeutic window for microglial modulation is rather limited and care must be taken to balance microglial activity.