The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism
Gernot Kleinberger 1 2 , Matthias Brendel 3 , Eva Mracsko 4 , Benedikt Wefers 5 6 , Linda Groeneweg 4 , Xianyuan Xiang 1 , Carola Focke 3 , Maximilian Deußing 3 , Marc Suárez-Calvet 1 5 , Fargol Mazaheri 5 , Samira Parhizkar 1 , Nadine Pettkus 1 , Wolfgang Wurst 2 5 6 7 , Regina Feederle 2 5 8 , Peter Bartenstein 2 3 , Thomas Mueggler 4 , Thomas Arzberger 5 9 10 , Irene Knuesel 4 , Axel Rominger 2 3 , Christian Haass
EMBO J
36(13)
1837-1853
2016
Zobrazit abstrakt
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. | 28559417
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TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance
Xianyuan Xiang 1 , Georg Werner 2 , Bernd Bohrmann 3 , Arthur Liesz 4 , Fargol Mazaheri 5 , Anja Capell 2 , Regina Feederle 6 , Irene Knuesel 3 , Gernot Kleinberger 7 , Christian Haass
EMBO Mol Med
8(9)
992-1004
2015
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Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease (AD). Antibodies against amyloid β-peptide (Aβ) bind to amyloid plaques and induce their clearance by microglia via Fc receptor-mediated phagocytosis. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and could result in reduced efficacy of antibody-mediated Aβ clearance. Recently, heterozygous mutations in the triggering receptor expressed on myeloid cells 2 (TREM2), a microglial gene involved in phagocytosis, were genetically linked to late onset AD Loss of TREM2 reduces the ability of microglia to engulf Aβ. We have now investigated whether loss of TREM2 affects the efficacy of immunotherapeutic approaches. We show that anti-Aβ antibodies stimulate Aβ uptake and amyloid plaque clearance in a dose-dependent manner in the presence or absence of TREM2. However, TREM2-deficient N9 microglial cell lines, macrophages as well as primary microglia showed significantly reduced uptake of antibody-bound Aβ and as a consequence reduced clearance of amyloid plaques. Titration experiments revealed that reduced efficacy of amyloid plaque clearance by Trem2 knockout cells can be compensated by elevating the concentration of therapeutic antibodies. | 27402340
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