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Kleinberger, G.* ; Brendel, M.D.* ; Mracsko, E.* ; Wefers, B. ; Groeneweg, L.* ; Xiang, X.* ; Focke, C.* ; Deußing, M.* ; Suárez-Calvet, M.* ; Mazaheri, F.* ; Parhizkar, S.* ; Pettkus, N.* ; Wurst, W. ; Feederle, R. ; Bartenstein, P.* ; Mueggler, T.* ; Arzberger, T.* ; Knuesel, I.* ; Rominger, A.* ; Haass, C.*

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

EMBO J., DOI: 10.15252/embj.201796516 (2017)
Verlagsversion Forschungsdaten DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Frontotemporal Dementia ; Neurodegeneration ; Neuroinflammation ; Regulated Intramembrane Proteolysis ; Trem2
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Verlag Wiley
Verlagsort Heidelberg, Germany
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)
CF Monoclonal Antibodies (CF-MAB)