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EMBO J. 2017 Jul 3;36(13):1837-1853. doi: 10.15252/embj.201796516. Epub 2017 May 30.

The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism.

Author information

1
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
2
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
3
Department of Nuclear Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
4
NORD Discovery & Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
5
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
6
Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
7
Technische Universität München, Freising-Weihenstephan, Germany.
8
Helmholtz Center Munich, German Research Center for Environmental Health, Institute for Diabetes and Obesity, Core Facility Monoclonal Antibody Development, Munich, Germany.
9
Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, Munich, Germany.
10
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany.
11
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany christian.haass@mail03.med.uni-muenchen.de.

Abstract

Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation. Consistent with a loss-of-function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p.T66M mutation. Trem2 p.T66M knock-in mice show delayed resolution of inflammation upon in vivo lipopolysaccharide stimulation and cultured macrophages display significantly reduced phagocytic activity. Immunohistochemistry together with in vivo TSPO small animal positron emission tomography (μPET) demonstrates an age-dependent reduction in microglial activity. Surprisingly, perfusion magnetic resonance imaging and FDG-μPET imaging reveal a significant reduction in cerebral blood flow and brain glucose metabolism. Thus, we demonstrate that a TREM2 loss-of-function mutation causes brain-wide metabolic alterations pointing toward a possible function of microglia in regulating brain glucose metabolism.

KEYWORDS:

TREM2; frontotemporal dementia; neurodegeneration; neuroinflammation; regulated intramembrane proteolysis

PMID:
28559417
PMCID:
PMC5494459
DOI:
10.15252/embj.201796516
[Indexed for MEDLINE]
Free PMC Article

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