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

Julia K. Götzl, Matthias Brendel, Georg Werner, Samira Parhizkar, Laura Sebastian Monasor, Gernot Kleinberger, Alessio Vittorio Colombo, Maximilian Deussing, Matias Wagner, Juliane Winkelmann, Janine Diehl-Schmid, Johannes Levin, Katrin Fellerer, Anika Reifschneider, Sebastian Bultmann, Peter Bartenstein, Axel Rominger, Sabina Tahirovic, Scott T. Smith, Charlotte MadoreOleg Butovsky, Anja Capell, Christian Haass

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

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 gene 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.

Original languageEnglish
Article numbere9711
JournalEMBO Molecular Medicine
Volume11
Issue number6
DOIs
StatePublished - Jun 2019

Keywords

  • TREM2
  • disease-associated and homeostatic microglial signatures
  • microglia
  • neurodegeneration
  • progranulin

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