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A combination drug therapy improves cognition and reverses gene expression changes in a mouse model of Huntington's disease

Morton, A. Jennifer, Hunt, Mark J., Hodges, Angela Kaye, Lewis, Paul David, Redfern, Amanda Jane, Dunnett, Stephen Bruce and Jones, Lesley 2005. A combination drug therapy improves cognition and reverses gene expression changes in a mouse model of Huntington's disease. European Journal of Neuroscience 21 (4) , pp. 855-870. 10.1111/j.1460-9568.2005.03895.x

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Abstract

Huntington's disease is a genetic disease caused by a single mutation. It is characterized by progressive movement, emotional and cognitive deficits. R6/2 mice transgenic for exon 1 of the HD gene with 150+ CAG repeats have a progressive neurological phenotype, including deterioration in cognitive function. The mechanism underlying the cognitive deficits in R6/2 mice is unknown, but dysregulated gene expression, reduced neurotransmitter levels and abnormal synaptic function are present before the cognitive decline becomes pronounced. Our goal here was to ameliorate the cognitive phenotype in R6/2 mice using a combination drug therapy (tacrine, moclobemide and creatine) aimed at boosting neurotransmitter levels in the brain. Treatment from 5 weeks of age prevented deterioration in two different cognitive tasks until at least 12 weeks. However, motor deterioration continued unabated. Microarray analysis of global gene expression revealed that many genes significantly up- or down-regulated in untreated R6/2 mice had returned towards normal levels after treatment, though a minority were further dysregulated. Thus dysregulated gene expression was reversed by the combination treatment in the R6/2 mice and probably underlies the observed improvements in cognitive function. Our study shows that cognitive decline caused by a genetic mutation can be slowed by a combination drug treatment, and gives hope that cognitive symptoms in HD can be treated.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: creatine; moclobemide; Morris water maze; neurodegeneration; R6/2; tacrine
ISSN: 0953-816X
Last Modified: 15 Dec 2017 08:34
URI: http://orca.cf.ac.uk/id/eprint/622

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