Pivotal role of microglial TREM2 in remyelination as revealed by multiparametric magnetic resonance imaging in the cuprizone mouse model

Identification: Mechling, Anna


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Pivotal role of microglial TREM2 in remyelination as revealed by multiparametric magnetic resonance imaging in the cuprizone mouse model
 
Anna Mechling1, Andreas Bruns1, Thomas Mueggler1, Basil Künnecke1, Rahel Zulliger1, Frédéric Knoflach1, Irene Knuesel1 and Eva Mracsko1
1Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
 
Demyelination and ensuing axonal damage are hallmarks of numerous neurodegenerative disorders. Novel treatment strategies seek to enhance remyelination and axonal recovery in order to restore functional impairment. TREM2 (triggering-receptor expressed on myeloid-cells-2) is a receptor expressed by microglia that has been implicated in the regulation of phagocytosis, migration and anti-inflammatory activity. Loss-of-function mutations of TREM2 can lead to Nasu-Hakola disease which presents - among others - with severe demyelination1. Here, we further elucidated the role of TREM2 in de- and remyelination processes via cuprizone-induced demyelination in transgenic mice carrying the human T66M mutation of TREM22. Longitudinal multiparametric magnetic resonance imaging (MRI) was performed for quantitative and structural assessment of myelin. Clinically relevant diffusion-based MRI readouts (diffusion tensor and kurtosis imaging) were back-translated and advanced in order to investigate myelin integrity of both white and grey matter. Homozygous TREM2 deficient animals showed exacerbated demyelination after cuprizone-feeding, moreover, they further deteriorated following cuprizone withdrawal in readouts for myelin content and integrity of both white and grey matter. Axonal conduction was assessed via electrophysiology for complementary confirmation of de- and remyelination processes on the functional level. Subsequent immunohistochemistry revealed lacking microglia clustering around the corpus callosum in TREM2 deficient animals that might hamper myelin debris clearance. Hence, our investigations show that TREM2 deficiency leads to insufficient microglial response to myelin damage accompanied by progressive myelin disintegration and absence of proper remyelination.
 
References:
1) Paloneva J et al. Am J Hum Genet. 2002 Sep;71(3):656-62.
2) Kleinberger G et al. EMBO J. 2017 Jul 3;36(13):1837-1853.
 

 

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