Behavioral improvement after chronic administration of coenzyme Q10 in P301S transgenic mice

Abstract

Coenzyme Q10 is a key component of the electron transport chain which plays an essential role in ATP production and also has antioxidant effects. Neuroprotective effects of coenzyme Q10 have been reported in both in vitro and in vivo models of neurodegenerative diseases. However, its effects have not been studied in cells or in animals with tau induced pathology. In this report, we administered coenzyme Q10 to transgenic mice with the P301S tau mutation, which causes fronto-temporal dementia in man. These mice develop tau hyperphosphorylation and neurofibrillary tangles in the brain. Coenzyme Q10 improved survival and behavioral deficits in the P301S mice. There was a modest reduction in phosphorylated tau in the cortex of P301S mice. We also examined the effects of coenzyme Q10 treatment on the electron transport chain enzymes, the mitochondrial antioxidant enzymes, and the tricarboxylic acid cycle. There was a significant increase in complex I activity and protein levels, and a reduction in lipid peroxidation. Our data show that coenzyme Q10 significantly improved behavioral deficits and survival in transgenic mice with the P301S tau mutation, upregulated key enzymes of the electron transport chain, and reduced oxidative stress.

Fig. 1

Administration of coenzyme Q10 improved survival and behavior in P301S mice. Cumulative survival curve (A) of P301S mice fed control and coenzyme Q10 (CoQ) diet. Coenzyme Q10 improved survival of P301S mice (n = 5). Ambulation (B), vertical movements (C), and anxiety (D) in the openfield for wild-type (Wt) and P301S mice (Tg) treated with control (Control) and coenzyme Q10 (CoQ) at 5 and 7 months of age. There was an increase in distance traveled, vertical movements, and time spent in the center in P301S mice as compared to wild-type littermates (Fisher PLSD, n = 12–20). Administration of coenzyme Q10 rescued this phenotype (n = 12–18). p < 0.05.

Fig. 2

Administration of coenzyme Q10 modestly reduced tau pathology in the cortex of P301S mice. AT8 staining in the cortex (A) and the hippocampus (C) of P301S mice (Tg) fed control and coenzyme Q10 (CoQ) diet. AT8 immunoreactivity expressed as percent area in the cortex (B) and the hippocampus (D) of P301S mice (Tg) fed control and coenzyme Q10 (CoQ) diet. Coenzyme Q10 did not affect tau phosphorylation in the hippocampus of P301S mice. However, there was a trend toward a decrease of percent area covered by AT8 immunoreactivity in the cortex of P301S mice (n = 3–4).

Fig. 3

Effects of coenzyme Q10 on the antioxidant system and oxidative stress. A) Enzymatic activity of glutathione reductase (GR), isocitrate dehydrogenase (ICD), and superoxide dismutase (SOD) in the cortex of P301S mice fed with control, coenzyme Q10 (CoQ) diet. B) Level of oxidized (GSSG) and reduced glutathione (GSH) in brains of P301S mice fed with control and coenzyme Q10 (CoQ) diet. The antioxidant system was not affected by coenzyme Q10 administration in P301S mice (n = 8–12). C) Level of malondialdehyde in brains of P301S mice fed with control and coenzyme Q10 (CoQ) diet. Administration of coenzyme Q10 reduced malondialdehyde level in P301S mice (n = 4–8). p < 0.05.

Fig. 4

Effects of coenzyme Q10 on the tricarboxylic acid cycle. Enzymatic activity of succinate dehydrogenase (SDH), aconitase (ACO), and citrate synthase (CS × 0.1) in the cortex of P301S mice fed with control and coenzyme Q10 (CoQ) diet. No differences were observed in tricarboxylic acid cycle enzymes after treatment with coenzyme Q10 (n = 3–6).

Fig. 5

Effects of coenzyme Q10 on the electron transport chain. Activity of complex I (A), levels of cytochrome c (B), ATPase (C), complex III (CIII) (C), complex IV (COX) (C) and complex I (CI) (C) in the cortex of P301S mice fed control and coenzyme Q10 (CoQ) diet. There was an increase in complex I activity and level in P301S mice after coenzyme Q10 treatment (n = 3–6). p < 0.05.