Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington's disease

Abstract

Controversies surround the usefulness of Coenzyme Q10 (CoQ10) in Huntington's disease (HD), an autosomal dominant, fatal, neurodegenerative disease with no cure or disease modifying treatment. CoQ10, an endogenous substrate for electron transport and an anti-oxidant, has been shown in some but not all studies to improve symptoms and survival in mouse models of HD. Previous studies have been conducted in fast-progressing models that better mimic the juvenile forms of HD than the much more common middle-age onset form, possibly accounting for mixed results. Establishing the usefulness of CoQ10 to alter HD disease course in a model that better recapitulates the progressive features of the human disorder is important because clinical trials of CoQ10, which is safe and well tolerated, are being planned in patients. The CAG140 knock-in (KI) mouse model of HD in which an expanded (approximately 120) CAG repeat is inserted in the mouse gene provides a model of the mutation in the proper genomic and protein context. These mice display progressive motor, cognitive and emotional anomalies, transcriptional disturbances and late striatal degeneration. Homozygote mutant CAG140 KI mice and wild-type littermates were fed CoQ10 (0.2%, 0.6%) in chow, and behavioral and pathological markers of disease were examined. CoQ10 improved early behavioral deficits and normalized some transcriptional deficits without altering huntingtin aggregates in striatum. The lower dose (0.2%) was more beneficial than 0.6%. Similar to previous studies, this low dose also induced deleterious effects in open field and rotarod in WT mice, however these effects are of unclear clinical significance in view of the excellent safety profile of CoQ10 in humans. These data confirm that CoQ10 may be beneficial in HD but suggest that maximum benefit may be observed when treatment is begun at early stages of the disease and that dosage may be critical.

Figure 1

Body weights of WT and KI male and female mice treated with 0.2% or 0.6% CoQ10 in chow or control chow. CoQ10-treated mice gained weight as expected, and no differences between treatment groups were noted. Body weights were analysed using a mixed generalized linear model ANOVAs in SAS using Bonferroni’s adjusted Student’s t-tests for post hoc analysis, graphs for WTs and KIs only shown, however weights of HET mice were also monitored (HET mice were not used for behavioral testing). WT males N=7–9; WT females N=6–12; KI males N=8–15; KI females N=9–14.

Figure 2

CoQ10 treatment (0.2%) rescued behavioral and rearing deficits in the open field in CAG140 KI mice. Mice were tested in the open field at 1 month of age, and control-treated KI mice showed reduced activity and rearing when compared to control-treated WT mice, as previously shown (Hickey et al in preparation). 0.2% CoQ10 (not 0.6%) prevented these deficits. In contrast, 0.2% CoQ10 impaired activity of WT mice. *p<0.05, **p<0.01 compared to same timepoint, control-treated WTs. ^p<0.05, ^^p<0.01 compared to same timepoint, control-treated KIs. WT n=13–21; KI n=15–25 for rearing. ANOVAs were performed using GBstat, followed by Fisher’s LSD for post hoc analysis. Data for activity were unavailable for 8 mice and for 1 mouse for rearing. The numbers 1, 2 and 3 denote the successive timebins (3 × 5 min, 15 min total) during the single exposure to the open field.

Figure 3

CoQ10 treatment rescued climbing activity in CAG140 mice. Mice were tested at 1.5 months of age. As previously reported (Hickey et al., 2008) control-treated CAG140 KI mice showed reduced climbing. 0.2% (but not 0.6%) CoQ10-treated KI mice were no longer different from either CoQ- or control-treated WT mice. *p<0.05 compared to control-treated WT mice. ^ p<0.05 compared to 0.6%-treated WT mice. ANOVA was performed using GBstat, followed by Fisher’s LSD for post hoc analysis. WT n=13–21; KI n=16–25.

Figure 4

CoQ10 prevented sensorimotor deficits on the pole task and motor deficits on the rotarod. A) Control-treated KI mice were impaired on the pole task, and both doses of CoQ10 prevented this deficit. B) Control-treated KI mice showed subtle deficits on the rotarod task (day 5), which were prevented by 0.2% CoQ10, but not by 0.6%. In contrast, WT mice were impaired by both doses of CoQ10. *p<0.05, **p<0.01 compared to control-treated WT. ANOVAs were performed using GBstat, followed by Fisher’s LSD for post hoc analysis. WT n= 13–21, KI n=15–25.

Figure 5

CoQ10 had no effect on aggregated mutant htt in striatum of 4.5 month old CAG140 KI mice. A, Vehicle, B, 0.2%, C, 0.6%. Density of diffusely stained nuclei, nuclei containing microaggregates, nuclei containing inclusions and neuropil aggregates were quantified in striatum from control-, 0.2%-, or 0.6% CoQ10-treated KI mice. No difference in density of any of these forms of aggregated htt was noted. n=6–9. Arrowheads denote diffusely stained nuclei containing inclusion bodies and microaggregates; full arrows denote diffusely-stained nuclei containing microaggregates; line arrows denote neuropil (cytoplasmic) aggregates.