Role of microglia in myelin turnover

by Shima Safaiyan
Doctoral thesis
Date of Examination:2015-09-21
Date of issue:2016-07-11
Advisor:Prof. Dr. Mikael Simons
Referee:Prof. Dr. Alexander Flügel
Referee:Prof. Dr. Holger Reichardt
Persistent Address: http://dx.doi.org/10.53846/goediss-5727

 

 

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Abstract

English

During development oligodendrocytes in the central nervous system (CNS) produce large amount of membrane to generate myelin which wraps around the axons. The synthesis, maintenance and turnover of such enormous amounts of myelin membranes are crucial for the maintenance of functional nerves. How molecules within the numerous layers of tightly compacted membrane get access to the degradation system for myelin turnover is not well known. In this work, we observed that microglia are in contact with myelin via their processes, and myelin fragments, generated due to myelin breakdown, are engulfed by these cells at 18 and 24 months of age. We could show that microglia are actively engaged in clearing away degenerated myelin in normal aging. To investigate the connection between myelin breakdown and phenotypic changes in microglia, demyelinating mouse models were analysed. The results showed that microglia in these mice specifically develop large amount of lysosomal inclusions that include internalized myelin components. In general, such inclusions are typically observed in aged post-mitotic cells and are called aging pigment or lipofuscin. To test whether impairing the lysosomal system is sufficient to induce an aging phenotype, we generated mice in which the lysosomal degradation pathway was specifically blocked in microglia. This was achieved by deleting the gene encoding Rab7 which is essential for maturation of lysosomes. In these mice, aged microglia with large inclusions was induced already when the mice were 10 weeks old. Already at 5 months of age the clearance function impaired and the number of extracellular myelin fragments increased. Using Rab7 KO mice we confirmed the role of microglia cells in clearing myelin in normal aging, and also induced a phenotype related to aging. These findings indicate that myelin breakdown can lead to lysosomal inclusion and impairs the clearance function of microglia. Since the clearance function is important for the cell function to fight against aging, our results may have important implication for multiple sclerosis and neurodegenerative disease associated with protein aggregation such as Alzheimer’s disease.
Keywords: Microglia; Myelin
 
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