A combination drug therapy improves cognition and reverses gene expression changes in a mouse model of Huntington's disease.
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.
Morton
A Jennifer
AJ
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1 PD, UK. ajm41@cam.ac.uk
Hunt
Mark J
MJ
Hodges
Angela K
AK
Lewis
Paul D
PD
Redfern
Amanda J
AJ
Dunnett
Stephen B
SB
Jones
Lesley
L
D000367:Age Factors; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000208:ethnology / Q000652:urine; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006816:Huntington Disease / Q000150:complications / Q000188:drug therapy* / Q000652:urine; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D018697:Nootropic Agents / Q000627:therapeutic use*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D045442:Rotarod Performance Test / Q000379:methods; D013037:Spatial Behavior / Q000502:physiology / Q000528:radiation effects; D018911:Trinucleotide Repeats / Q000235:genetics
D018377:Neurotransmitter Agents; D018697:Nootropic Agents; D012333:RNA, Messenger; D005947:Glucose