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 Madore, Oleg Butovsky, Anja Capell, Christian Haass
EMBO Mol Med. 2019-05-23; 11(6):
DOI: 10.15252/emmm.201809711

PubMed
Read on PubMed



1. EMBO Mol Med. 2019 Jun;11(6). pii: e9711. doi: 10.15252/emmm.201809711.

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

Götzl JK(1), Brendel M(2), Werner G(1), Parhizkar S(1), Sebastian Monasor L(3),
Kleinberger G(1)(4), Colombo AV(3), Deussing M(2), Wagner M(5)(6)(7), Winkelmann
J(5)(6)(7), Diehl-Schmid J(8), Levin J(3)(9), Fellerer K(1), Reifschneider A(1),
Bultmann S(10), Bartenstein P(2)(4), Rominger A(2)(4), Tahirovic S(3), Smith
ST(11), Madore C(11), Butovsky O(11)(12), Capell A(13), Haass C(13)(3)(4).

Author information:
(1)Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine,
Ludwig-Maximilians-Universität München, Munich, Germany.
(2)Department of Nuclear Medicine, University Hospital,
Ludwig-Maximilians-Universität München, Munich, Germany.
(3)German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
(4)Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
(5)Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.
(6)Institut of Human Genetics, Technische Universität München, Munich, Germany.
(7)Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
(8)Department of Psychiatry, Technische Universität München, Munich, Germany.
(9)Department of Neurology, University Hospital, Ludwig-Maximilians-Universität
München, Munich, Germany.
(10)Department of Biology and Center for Integrated Protein Science Munich
(CIPSM), Ludwig Maximilians-Universität München, Munich, Germany.
(11)Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
(12)Evergrande Center for Immunologic Diseases, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA.
(13)Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of
Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

.

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.

© 2019 The Authors. Published under the terms of the CC BY 4.0 license.

DOI: 10.15252/emmm.201809711
PMCID: PMC6554672
PMID: 31122931 [Indexed for MEDLINE]

Know more about