Brain, Vol. 126, No. 4, 974-987,
April 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg089
Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis
1 Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, 2 CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton, UK, 3 Department of Genetics, St Jude Children’s Hospital, Memphis, TN, USA
Correspondence to: Dr Frances M. Platt, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK E-mail: fran{at}glycob.ox.ac.uk
Mouse models of the GM2 gangliosidoses [Tay-Sachs, late onset Tay-Sachs (LOTS), Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is a common neuro-inflammatory component to these disorders. During the disease course, we have: (i) examined the expression of a number of inflammatory markers in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine, CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor 
(TNF), transforming growth factor (TGFß1) and interleukin 1ß (IL1ß)]; and (iii) studied blood-brain barrier (BBB) integrity. The kinetics of apoptosis and the expression of Fas and TNF-R1 were also assessed. In all symptomatic mouse models, a progressive increase in local microglial activation/expansion and infiltration of inflammatory cells was noted. Altered BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice. Progressive CNS inflammation coincided with the onset of clinical signs in these mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of the inflammatory process and disease pathogenesis. These data suggest that inflammation may play an important role in the pathogenesis of the gangliosidoses.
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