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

Götzl, Julia K, Brendel, Matthias, Werner, Georg, Parhizkar, Samira, Sebastian Monasor, Laura, Kleinberger, Gernot, Colombo, Alessio‐Vittorio, Deussing, Maximilian, Wagner, Matias, Winkelmann, Juliane, Diehl‐Schmid, Janine, Levin, Johannes, Fellerer, Katrin, Reifschneider, Anika, Bultmann, Sebastian, Bartenstein, Peter, Rominger, Axel, Tahirovic, Sabina, Smith, Scott T, Madore, Charlotte, Butovsky, Oleg, Capell, Anja, Haass, Christian·2019·EMBO Molecular Medicine
DOI 10.15252/emmm.201809711PMC PMC6554672
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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.

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Metadata

Authors
Götzl, J. K., Brendel, M., Werner, G., Parhizkar, S., Sebastian Monasor, L., Kleinberger, G., Colombo, A., Deussing, M., Wagner, M., Winkelmann, J., Diehl‐Schmid, J., Levin, J., Fellerer, K., Reifschneider, A., Bultmann, S., Bartenstein, P., Rominger, A., Tahirovic, S., Smith, S. T., Madore, C., Butovsky, O., Capell, A., & Haass, C.
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-05-23
Volume
11
Issue
6
ISSN
  • 1757-4676
  • 1757-4684
DOI
10.15252/emmm.201809711
PMC
PMC6554672
Cited by
118
References
36
Language
en
Licence
Funders
  • HHS|NIH|National Institute of Neurological Disorders and Stroke (R01 NS088137, R21NS104609, R21NS101673)
  • Nancy Davis Foundation for Multiple Sclerosis Faculty Award
  • Cure Alzheimer's Fund
  • Amyotrophic Lateral Sclerosis Association
  • Hans and Ilse Breuer Foundation
  • Bundesministerium für Bildung und Forschung (FTLDc 01GI1007A)
  • HHS|National Institutes of Health (NEY (R01 EY027921))
  • HHS|NIH|National Institute on Aging (R01 AG051812, R01 AG054672)
  • Deutsche Forschungsgemeinschaft (EXC 1010 SyNergy, HA1737/16‐1, BR4580/1‐1, RO5194/1‐1)
  • NOMIS Foundation
  • National Multiple Sclerosis Society (5092A1)
  • Sanofi

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