Exercise-induced neuroprotection of hippocampus in APP/PS1 transgenic mice via upregulation of mitochondrial 8-oxoguanine DNA glycosylase

Abstract

Improving mitochondrial function has been proposed as a reasonable therapeutic strategy to reduce amyloid-β (Aβ) load and to modify the progression of Alzheimer's disease (AD). However, the relationship between mitochondrial adaptation and brain neuroprotection caused by physical exercise in AD is poorly understood. This study was undertaken to investigate the effects of long-term treadmill exercise on mitochondrial 8-oxoguanine DNA glycosylase-1 (OGG1) level, mtDNA oxidative damage, and mitochondrial function in the hippocampus of APP/PS1 transgenic mouse model of AD. In the present study, twenty weeks of treadmill training significantly improved the cognitive function and reduced the expression of Aβ-42 in APP/PS1 transgenic (Tg) mice. Training also ameliorated mitochondrial respiratory function by increasing the complexes I, and IV and ATP synthase activities, whereas it attenuated ROS generation and mtDNA oxidative damage in Tg mice. Furthermore, the impaired mitochondrial antioxidant enzymes and mitochondrial OGG1 activities seen in Tg mice were restored with training. Acetylation level of mitochondrial OGG1 and MnSOD was markedly suppressed in Tg mice after exercise training, in parallel with increased level of SIRT3. These findings suggest that exercise training could increase mtDNA repair capacity in the mouse hippocampus, which in turn would result in protection against AD-related mitochondrial dysfunction and phenotypic deterioration.

Figure 1

Effects of 20 weeks of treadmill exercise training on behavioral functions: (a) spontaneous alternation behavior; (b) total number of arm entries; (c) retention latency time. SED-Wt: sedentary wild-type mice. EXE-Wt: exercise-trained wild-type mice. SED-Tg: sedentary APP/PS1 transgenic mice. EXE-Tg: exercise-trained APP/PS1 transgenic mice. n = 32 for all independent experiments. Data are mean ± SD. ^** P < 0.01, compared to SED-WT group. ^# P < 0.05; ^## P < 0.01, compared to SED-Wt or SED-Tg group. n.s., nonsignificant.

Figure 2

Effects of 20 weeks of treadmill exercise training on Aβ-42 protein level with Western blot. Group identities are the same as those in Figure 1. Hippocampus from four mice in one group was pooled for each sample, n = 8 for all independent experiments. Data are mean ± SD. ^** P < 0.01, compared to SED-WT group. ^## P < 0.01, compared to SED-Tg group. n.s., nonsignificant.

Figure 3

Effects of 20 weeks of treadmill exercise training on mitochondrial state 3 respiration rate (a), state 4 respiration rate (b), and respiratory control ratio (RCR) (c). Group identities are the same as those in Figure 1. Hippocampus from four mice in one group was pooled and mitochondria were isolated for each sample, n = 8 for all independent experiments. Data are mean ± SD. ^* P < 0.05; ^** P < 0.01, compared to SED-WT group. ^# P < 0.05, compared to SED-Wt or SED-Tg group. n.s., nonsignificant.

Figure 4

Effects of 20 weeks of treadmill exercise training on activities of mitochondrial complex I (a), complex II (b), complex III, (c), complex IV (d), and ATP synthase activity (e). Group identities are the same as those in Figure 1. Hippocampus from four mice in one group was pooled and mitochondria were isolated for each sample, n = 8 for all independent experiments. Data are mean ± SD. ^** P < 0.01 compared to SED-WT group. ^# P < 0.05; ^## P < 0.01, compared to SED-Wt or SED-Tg group. n.s., nonsignificant.

Figure 5

Effect of 20 weeks of treadmill exercise training on mitochondrial ROS generation (a) and 8-oxodG content of the mtDNA (b). Group identities are the same as those in Figure 1. Hippocampus from four mice in one group was pooled and mitochondria were isolated for each sample, n = 8 for all independent experiments. Data are mean ± SD. ^* P < 0.05; ^** P < 0.01, compared to SED-WT group. ^# P < 0.05; ^## P < 0.01, compared to SED-Wt or SED-Tg group. n.s., nonsignificant.

Figure 6

Effect of 20 weeks of treadmill exercise training on mitochondrial MnSOD (a) and GPx activity (b). Group identities are the same as those in Figure 1. Hippocampus from four mice in one group was pooled and mitochondria were isolated for each sample, n = 8 for all independent experiments. Data are mean ± SD. ^* P < 0.05; ^** P < 0.01, compared to SED-WT or SED-Tg group. ^# P < 0.05; ^## P < 0.01, compared to SED-Wt or SED-Tg group. n.s., nonsignificant.

Figure 7

Effect of 20 weeks of treadmill exercise training on mitochondrial OGG1 activity (a) and protein content (b). Group identities are the same as those in Figure 1. Hippocampus from four mice in one group was pooled and mitochondria were isolated for each sample, n = 8 for all independent experiments. Data are mean ± SD. ^* P < 0.05, ^** P < 0.01, compared to SED-WT group. ^## P < 0.01, compared to SED-Wt or SED-Tg group. n.s., nonsignificant.

Figure 8

Effect of 20 weeks of treadmill exercise training on mitochondrial SIRT3 protein content (a), mitochondrial OGG1 acetylation level (b), and MnSOD acetylation level (c). Group identities are the same as those in Figure 1. Hippocampus from four mice in one group was pooled and mitochondria were isolated for each sample, n = 8 for all independent experiments. Data are mean ± SD. ^** P < 0.01, compared to SED-WT group. ^## P < 0.01, compared to SED-Wt or SED-Tg group. n.s., nonsignificant.

Figure 9

Possible mechanism of exercise training-induced neuroprotective effects in Alzheimer's disease (AD).