The role of astrocytes in murine models of toxic demyelination

by Lena Menken
Doctoral thesis
Date of Examination:2016-06-22
Date of issue:2016-08-30
Advisor:Prof. Dr. Wolfgang Brück
Referee:Prof. Dr. Wolfgang Brück
Referee:Prof. Dr. Mikael Simons
Persistent Address: http://dx.doi.org/10.53846/goediss-5792

 

 

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Abstract

English

In demyelinating diseases such as multiple sclerosis (MS) activated astrocytes, characterised by up-regulation of the intermediate filament glial fibrillary acidic protein (GFAP), were shown to have beneficial as well as detrimental effects on demyelination. Therefore, this study aims to investigate the effect of enhanced GFAP expression in astrocytes on the interaction with oligodendrocytes and microglia during demyelination. To address this question, toxic demyelination was induced in transgenic mice with human (h)GFAP overexpression using two different approaches: the cuprizone model and intracerebral injection of lysolecithin. The results demonstrated that an enhanced hGFAP expression in astrocytes has protective effects in both models, resulting in reduced demyelination and decreased oligodendrocyte loss during cuprizone treatment. Furthermore, this study demonstrated that enhanced hGFAP expression in astrocytes reduced microglia infiltration during cuprizone treatment. This observation might be explained by decreased mRNA expression of the chemokines CCL2 and CXCL10 in transgenic mice. Both chemokines were demonstrated to regulate microglia recruitment. Additionally, this study demonstrated that NF-κB activity was reduced in vitro and in vivo in astrocytes of transgenic mice with enhanced GFAP expression. The nuclear transcription factor (NF)-κB signalling pathway was shown to regulate the expression of CCL2 and CXCL10 in reactive astrocytes. This study confirms that reactive astrocytes have protective effects in models of toxic demyelination in vivo. Enhanced hGFAP expression seems to modulate astrocytic chemokine expression, presumably via a reduced activation of the NF-κB pathway. The reduction of CCL2 and CXCL10 expression levels results in reduced microglia recruitment which may lead to reduced demyelination.
Keywords: astrocytes; glial fibrillary acidic protein; multiple sclerosis
 
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