Neuroprotective Benefits of Exercise and MitoQ on Memory Function, Mitochondrial Dynamics, Oxidative Stress, and Neuroinflammation in D-Galactose-Induced Aging Rats.

Exercise and antioxidants have health benefits that improve cognitive impairment and may act synergistically. In this study, we examined the effects of treadmill exercise (TE) and mitochondria-targeted antioxidant mitoquinone (MitoQ), individually or combined, on learning and memory, mitochondrial dynamics, NADPH oxidase activity, and neuroinflammation and antioxidant activity in the hippocampus of D-galactose-induced aging rats. TE alone and TE combined with MitoQ in aging rats reduced mitochondrial fission factors (Drp1, Fis1) and increased mitochondrial fusion factors (Mfn1, Mfn2, Opa1). These groups also exhibited improved NADPH oxidase activity and antioxidant activity (SOD-2, catalase). TE or MitoQ alone decreased neuroinflammatory response (COX-2, TNF-α), but the suppression was greater with their combination. In addition, aging-increased neuroinflammation in the dentate gyrus was decreased in TE but not MitoQ treatment. Learning and memory tests showed that, contrarily, MitoQ alone demonstrated some similar effects to TE but not a definitive improvement. In conclusion, this study demonstrated that MitoQ exerted some positive effects on aging when used as an isolated treatment, but TE had a more effective role on cognitive impairment, oxidative stress, inflammation, and mitochondria dysfunction. Our findings suggest that the combination of TE and MitoQ exerted no synergistic effects and indicated regular exercise should be the first priority in neuroprotection of age-related cognitive decline.

The Prospects of the Two-Day Cardiopulmonary Exercise Test (CPET) in ME/CFS Patients: A Meta-Analysis.

BACKGROUND: The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is problematic due to the lack of established objective measurements. Postexertional malaise (PEM) is a hallmark of ME/CFS, and the two-day cardiopulmonary exercise test (CPET) has been tested as a tool to assess functional impairment in ME/CFS patients. This study aimed to estimate the potential of the CPET. METHODS: We reviewed studies of the two-day CPET and meta-analyzed the differences between ME/CFS patients and controls regarding four parameters: volume of oxygen consumption and level of workload at peak (VO2peak, Workloadpeak) and at ventilatory threshold (VO2@VT, Workload@VT). RESULTS: The overall mean values of all parameters were lower on the 2nd day of the CPET than the 1st in ME/CFS patients, while it increased in the controls. From the meta-analysis, the difference between patients and controls was highly significant at Workload@VT (overall mean: -10.8 at Test 1 vs. -33.0 at Test 2, p < 0.05), which may reflect present the functional impairment associated with PEM. CONCLUSIONS: Our results show the potential of the two-day CPET to serve as an objective assessment of PEM in ME/CFS patients. Further clinical trials are required to validate this tool compared to other fatigue-inducing disorders, including depression, using well-designed large-scale studies.

Effects of treadmill exercise on the regulatory mechanisms of mitochondrial dynamics and oxidative stress in the brains of high-fat diet fed rats.

PURPOSE: The purpose of this study was to investigate the effects of treadmill exercise on oxidative stress in the hippocampal tissue and mitochondrial dynamic-related proteins in rats fed a long-term high-fat diet (HFD). METHODS: Obesity was induced in experimental animals using high fat feed, and the experimental groups were divided into a normal diet-control (ND-CON; n=12), a high fat diet-control (HFD-CON; n=12) and a high fat diet-treadmill exercise (HFD-TE; n=12) group. The rats were subsequently subjected to treadmill exercise (progressively increasing load intensity) for 8 weeks (5 min at 8 m/min, then 5 min at 11 m/min, and finally 20 min at 14 m/min). We assessed weight, triglyceride (TG) concentration, total cholesterol (TC), area under the curve, homeostatic model assessment of insulin resistance, and AVF/body weight. Western blotting was used to examine expression of proteins related to oxidative stress and mitochondrial dynamics, and immunohistochemistry was performed to examine the immunoreactivity of gp91phox. RESULTS: Treadmill exercise effectively improved the oxidative stress in the hippocampal tissue, expression of mitochondrial dynamic-related proteins, and activation of NADPH oxidase (gp91phox) and induced weight, blood profile, and abdominal fat loss. CONCLUSION: Twenty weeks of high fat diet induced obesity, which was shown to inhibit normal mitochondria fusion and fission functions in hippocampal tissues. However, treadmill exercise was shown to have positive effects on these pathophysiological phenomena. Therefore, treadmill exercise should be considered during prevention and treatment of obesity-induced metabolic diseases.

Resistance Exercise Improves Mitochondrial Quality Control in a Rat Model of Sporadic Inclusion Body Myositis.

BACKGROUND: Mitochondrial dysfunction is implicated in the pathogenesis of multiple muscular diseases, including sporadic inclusion body myositis (s-IBM), the most common aging-related muscle disease. However, the factors causing mitochondrial dysfunction in s-IBM are unknown. OBJECTIVE: We hypothesized that resistance exercise (RE) may alleviate muscle impairment by improving mitochondrial function via reducing amyloid-beta (Aß) accumulation. METHODS: Twenty-four male Wistar rats were randomized to a saline-injection control group (sham, n = 8), a chloroquine (CQ) control group (CQ-CON, n = 8), and a CQ plus RE group (CQ-RE, n = 8) in which rats climbed a ladder with weight attached to their tails 9 weeks after starting CQ treatment. RESULTS: RE markedly inhibited soleus muscle atrophy and muscle damage. RE reduced CQ-induced Aß accumulation, which resulted in decreased formation of rimmed vacuoles and mitochondrial-mediated apoptosis. Most importantly, the decreased Aß accumulation improved both mitochondrial quality control (MQC) through increased mitochondrial biogenesis and mitophagy, and mitochondrial dynamics. Furthermore, RE-mediated reduction of Aß accumulation elevated mitochondrial oxidative capacity by upregulating superoxide dismutase-2, catalase, and citrate synthase via activating sirtuin 3 signaling. CONCLUSION: RE enhances mitochondrial function by improving MQC and mitochondrial oxidative capacity via reducing Aß accumulation, thereby inhibiting CQ-induced muscle impairment, in a rat model of s-IBM.

Neuroprotective effect of treadmill exercise against blunted brain insulin signaling, NADPH oxidase, and Tau hyperphosphorylation in rats fed a high-fat diet.

Obesity induces oxidative stress by causing hyperglycemia and insulin resistance, while contributing to cognitive and memory decline by inducing insulin resistance in the brain and hyperphosphorylation of Tau proteins. We aimed to investigate the effects of treadmill exercise in improving these obesity-induced pathological phenomena. Sprague-Dawley rats aged 20 weeks were fed a high-fat diet (HFD) for 20 weeks to induce obesity. The rats were subsequently subjected to treadmill exercise (progressively increasing load intensity) for 8 weeks. The rats were divided into three groups: normal diet-control (n = 15), HFD-control (n = 15), and HFD-treadmill exercise (n = 15). We performed water maze and passive avoidance tests and assessed weight, area under the curve, homeostatic model assessment of insulin resistance, and abdominal visceral fat/body weight. Western blot was used to examine protein expression related to brain insulin signaling, tau hyperphosphorylation, and NADPH oxidase, and immunohistochemistry was performed to examine the immunoreactivity of p-Tau (Ser 202/Thr 205) and p22-phox. Treadmill exercise effectively rescued brain insulin signaling, hyperphosphorylation and aggregation of Tau protein, and NADPH oxidase activation in the high fat diet group. Furthermore, it improved insulin resistance inhibitors, decreased abdominal fat mass, inhibited weight gain, and rescued learning and memory. Obesity-induced insulin resistance contributes to cognitive decline, such as reduced learning and memory, but physical activity, such as treadmill exercise, was found to have a positive effect on brain function by improving thesepathological phenomena. Therefore, we suggest that treadmill exercise must be considered in the prevention and treatment of metabolic and neurodegenerative diseases.

Effects of treadmill exercise on PI3K/AKT/GSK-3ß pathway and tau protein in high-fat diet-fed rats.

PURPOSE: This study aimed to clearly evaluate the effects of obesity on cerebral health. Thus, we induced obesity in rats using a long-term high-fat diet (HFD), then investigated its effects on insulin signaling and tau hyperphosphorylation. Additionally, we examined the effects of 8 weeks of treadmill exercise (TE) on insulin signaling and tau hyperphosphorylation. METHODS: Rats were separated into Normal Diet-Control, HFD-Control, and HFD-TE groups. TE loads were gradually increased. A passive avoidance test was used to evaluate cognitive function. Western blots were used to examine the abundance of the insulin receptor,phosphoinositide 3-kinase, protein kinase B, glycogen synthase kinase-3ß, and tau proteins in the cerebral cortex; immunohistochemical analyses were used to examine the abundance of hyperphosphorylated tau in the cerebral cortex. RESULTS: TE in HFD-fed rats resulted in a significant lowering of bodyweight, abdominal visceral fat (AVF), the area under the glucose response curve, and the homeostatic model assessment-insulin resistance index, while it improved working memory. In addition, TE in HFD-fed rats decreased tau hyperphosphorylation and aggregation, while increasing insulin signaling-related protein activity. CONCLUSION: After a 20-week HFD, the experimental animals exhibited increased weight, as well as impaired insulin resistance and blood glucose metabolism. HFD rats demonstrated abnormal insulin signaling and tau hyperphosphorylation in the cerebral cortex, as well as memory impairments that suggested reduced cerebral function. However, TE reduced AVF, improved insulin resistance in the peripheral tissues by increasing insulin sensitivity, and alleviated memory impairments by restoring insulin signaling and reducing tau hyperphosphorylation in the cerebral cortex.

Effect of Resistance Exercise on Muscle Metabolism and Autophagy in sIBM.

PURPOSE: Sporadic inclusion body myositis (sIBM), a muscular degenerative disease in the elderly, is an inflammatory myopathy characterized by muscle weakness in the wrist flexor, quadriceps, and tibialis anterior muscles. We aimed to identify the therapeutic effect of resistance exercise (RE) in improving sIBM symptoms in an sIBM animal model. METHODS: Six-week-old male Wistar rats were divided into a sham group (sham, n = 12), chloroquine-control group (CQ-con, n = 12), and chloroquine-RE group (CQ-RE, n = 12). The rats were subjected to 1 wk of exercise adaptation and 8 wk of exercise (three sessions per week). Protein expression was measured by Western blotting. Rimmed vacuoles (RV) were identified by hematoxylin and eosin staining and modified Gömöri trichrome staining, and amyloid deposition was examined by Congo red staining. RESULTS: The effects of CQ and RE differed depending on myofiber characteristics. Soleus muscles showed abnormal autophagy in response to CQ, which increased RV generation and amyloid-ß accumulation, resulting in atrophy. RE generated RV and decreased amyloid deposition in soleus muscles and also improved autophagy without generating hypertrophy. This reduced the atrophy signal transduction, resulting in decreased atrophy compared with the CQ-con group. Despite no direct effect of CQ, flexor hallucis longus muscles showed loss of mass because of reduced activity or increased inflammatory response; however, RE increased the hypertrophy signal, resulting in reduced autophagy and atrophy. CONCLUSIONS: These results demonstrate that RE had a preventive effect on sIBM induced by CQ treatment in an animal model. However, because the results were from an animal experiment, a more detailed study should be conducted over a longer period, and the effectiveness of different RE programs should also be investigated.

Treadmill exercise decreases amyloid-ß burden possibly via activation of SIRT-1 signaling in a mouse model of Alzheimer's disease.

Accumulation of amyloid-ß (Aß) correlates significantly with progressive cognitive deficits, a main symptom of Alzheimer's disease (AD). Although treadmill exercise reduces Aß levels, the molecular mechanisms underlying the effects are not fully understood. We hypothesize that treadmill exercise decreases Aß production and alleviates cognitive deficits by activating the non-amyloidogenic pathway via SIRT-1 signaling. Treadmill exercise improved cognitive deficits and alleviated neurotoxicity. Most importantly, treadmill exercise increased SIRT-1 level, which subsequently resulted in increased ADAM-10 level by down-regulation of ROCK-1 and upregulation of RARß, ultimately facilitating the non-amyloidogenic pathway. Treadmill exercise-induced activation in SIRT-1 level also elevated PGC-1α level and reduced BACE-1 and C-99 level, resulting in inhibition of the amyloidogenic pathway. Treadmill exercise may thus inhibit Aß production via upregulation of SIRT-1, which biases amyloid precursor protein processing toward the non-amyloidogenic pathway. This study provides novel and valuable insight into the molecular mechanisms possibly by which treadmill exercise reduces Aß production.

Neuroprotective effects of endurance exercise against neuroinflammation in MPTP-induced Parkinson's disease mice.

Parkinson's disease (PD) is one of the main degenerative neurological disorders accompanying death of dopaminergic neurons prevalent in aged population. Endurance exercise (EE) has been suggested to confer neurogenesis and mitigate the degree of seriousness of PD. However, underlying molecular mechanisms responsible for exercise-mediated neuroprotection against PD remain largely unknown. Given the relevant interplay between elevated α-synuclein and neuroinflammation in a poor prognosis and vicious progression of PD and anti-inflammatory effects of EE, we hypothesized that EE would reverse motor dysfunction and cell death caused by PD. To this end, we chose a pharmacological model of PD (e.g., chronic injection of neurotoxin MPTP). Young adult male mice (7 weeks old) were randomly divided into three groups: sedentary control (C, n=10), MPTP (M, n=10), and MPTP + endurance exercise (ME, n=10). Our data showed that EE restored motor function impaired by MPTP in parallel with reduced cell death. Strikingly, EE exhibited a significant reduction in α-synuclein protein along with diminished pro-inflammatory cytokines (i.e., TNF-α and IL-1ß). Supporting this, EE prevented activation of Toll like receptor 2 (TLR2) downstream signaling cascades such as MyD88, TRAF6 and TAK-1 incurred by in MPTP administration in the striatum. Moreover, EE reestablished tyrosine hydroxylase at levels similar to C group. Taken together, our data suggest that an EE-mediated neuroprotective mechanism against PD underlies anti-neuroinflammation conferred by reduced levels of α-synuclein. Our data provides an important insight into developing a non-pharmacological countermeasure against neuronal degeneration caused by PD.

The effects of senior brain health exercise program on basic physical fitness, cognitive function and BDNF of elderly women - a feasibility study.

PURPOSE: This study was to investigate the impacts of senior brain heath exercise (SBHE) program for 12 weeks to basic active physical fitness, cognitive function and brain derived neurotrophic factor (BDNF) in elderly women. METHODS: Subject of this study is total of 24 women in the age of 65-79 who can conduct normal daily activity and communication but have not participated in regular exercise in recent 6 months. The study groups were divided into an exercise group (EG, n=13) and a control group (CG, n=11). The exercise program was consisted of SBHE, and training frequency was 4 times weekly, of which training time was a total of 50 minutes each time in level of intensity of 9-14 by rating of perceived exertion (RPE). RESULTS: First, 12-week SBHE program has shown statistical increase in basic physical fitness in the EG comparing with the CG, such as lower body strength, upper body strength and aerobic endurance, but not in flexibility, agility and dynamic balance. Second, in the case of Mini-mental state examination Korean version (MMSE-K) and BDNF, it showed that there was a statistically significant increase in the EG comparing with the CG. CONCLUSION: In this study, 12-week SBHE program has resulted in positive effect on change of basic physical fitness (strength and aerobic endurance), cognitive function and BDNF. If above program adds movements that can enhance flexibility, dynamic balance and agility, this can be practical exercise program to help seniors maintain overall healthy lifestyle.

Cardiac Kinetophagy Coincides with Activation of Anabolic Signaling.

PURPOSE: Growing evidence has shown that endurance exercise is a strong inducer of autophagy in various tissues. Thus, we define here endurance exercise-induced autophagy as "kinetophagy" derived from the Greek terms "kineto" (movement), "auto" (self), and "phagy" (eating). Currently, the exact cellular mechanisms responsible for kinetophagy remain unclear; hence, we examined kinetophagy signaling transduction pathways occurring during acute endurance exercise (AEE). METHODS: C57BL/6 mice were randomly assigned to either AEE (n = 7) or control sedentary group (CON, n = 7). After 5 d of treadmill running acclimation, mice performed 60 min of a single bout of treadmill running at 12 m · min(-1) on a 0% grade. Hearts were excised immediately 1 h after exercise and homogenized for Western blot analyses. RESULTS: Our data showed that AEE promoted kinetophagy flux (an increase in LC3-II to LC3-I ratio and LC3-II levels and a reduction in p62 levels) with Beclin-1 levels suppressed but Atg7 levels elevated compared with those in the sedentary group. We also observed that AEE increased lysosome-associated membrane protein and cathepsin L, linked to the termination process of autophagy, and that AEE augmented potent autophagy inducers (i.e., adenosine monophosphate kinase phosphorylation, BNIP3, and HSP70). Moreover, we found that exercise-mediated BNIP3 upregulation is associated with hypoxia-inducing factor 1α rather than FoxO3a. Intriguingly, we found for the first time that kinetophagy parallels with anabolic signaling activation (Akt and mammalian target of rapamycin). CONCLUSIONS: Our findings provide evidence that AEE results in kinetophagy without a time-associated elevation in Beclin-1 but with the presence of Akt-mTOR activation and that AEE-induced activation of anabolic signaling is not associated with kinetophagy promotion.

Effect of treadmill exercise on PI3K/AKT/mTOR, autophagy, and Tau hyperphosphorylation in the cerebral cortex of NSE/htau23 transgenic mice.

PURPOSE: Neurofibrillary tangles, one of pathological features of Alzheimer's disease, are produced by the hyperphosphorylation and aggregation of tau protein. This study aimed to investigate the effects of treadmill exercise on PI3K/AKT/mTOR signal transmission, autophagy, and cognitive ability that are involved in the hyperphosphorylation and aggregation of tau protein. METHODS: Experimental animals (NSE/htau23 mice) were divided into non-transgenic control group (Non-Tg-Control; CON; n = 7), transgenic control group (Tg-CON; n = 7), and transgenic exercise group (Tg-Treadmill Exercise; TE; n = 7). The Tg-TE group was subjected to treadmill exercise for 12 weeks. After the treadmill exercise was completed, the cognitive ability was determined by conducting underwater maze tests. Western blot was conducted to determine the phosphorylation status of PI3K/AKT/mTOR proteins and autophagy-related proteins (Beclin-1, p62, LC3-B); hyperphosphorylation and aggregation of tau protein (Ser199/202, Ser404, Thr231, PHF-1); and phosphorylation of GSK-3ß, which is involved in the phosphorylation of tau protein in the cerebral cortex of experimental animals. RESULTS: In the Tg-TE group that was subjected to treadmill exercise for 12 weeks, abnormal mTOR phosphorylation of PI3K/AKT proteins was improved via increased phosphorylation and its activity was inhibited by increased GSK-3ß phosphorylation compared with those in the Tg-CON group, which was used as the control group. In addition, the expression of Beclin-1 protein involved in autophagosome formation was increased in the Tg-TE group compared with that in the Tg-CON group, whereas that of p62 protein was reduced in the Tg-TE group compared with that in the Tg-CON group. Autophagy was activated owing to the increased expression of LC3-B that controls the completion of autophagosome formation. The hyperphosphorylation and aggregation (Ser199/202, Ser404, Thr231, PHF-1) of tau protein was found to be reduced in the Tg-TE group compared with that in the Tg-CON group. Furthermore, in the underwater maze test, the Tg-TE group showed a reduced escape time and distance compared with those of the Tg-CON group, suggesting that learning and cognitive ability were improved. CONCLUSION: These findings suggest that aerobic exercise such as treadmill exercise might be an effective approach to ameliorate the pathological features (or neurofibrillary tangles) of Alzheimer's disease.

Effects of treadmill exercise on brain insulin signaling and ß-amyloid in intracerebroventricular streptozotocin induced-memory impairment in rats.

PURPOSE: The purpose of the study is to explore effect of 6 weeks treadmill exercise on brain insulin signaling and ß-amyloid(Aß). METHODS: The rat model of Alzheimer's disease(AD) used in the present study was induced by the intracerebroventricular(ICV) streptozotocin(STZ). To produce the model of animal with AD, STZ(1.5mg/kg) was injected to a cerebral ventricle of both cerebrums of Sprague-Dawley rat(20 weeks). The experimental animals were divided into ICV-Sham(n=7), ICV-STZ CON(n=7), ICV-STZ EXE(n=7). Treadmill exercise was done for 30 min a day, 5 days a week for 6 weeks. Passive avoidance task was carried out before and after treadmill exercise. RESULTS: The results of this study show that treadmill exercise activated Protein kinase B(AKT)/ Glycogen synthase kinase 3α (GSK3α), possibly via activation of insulin receptor(IR) and insulin receptor substrate(IRS) and reduced Aß in the brain of ICV-STZ rats. More interestingly, treadmill exercise improved cognitive function of ICV-STZ rats. Finally, physical exercise or physical activity gave positive influences on brain insulin signaling pathway. CONCLUSION: Therefore, treadmill exercise can be applied to improve AD as preventive and therapeutic method.

The effect of treadmill exercise on inflammatory responses in rat model of streptozotocin-induced experimental dementia of Alzheimer's type.

PURPOSE: The aim of this study was to investigate the effect of treadmill exercise on inflammatory response in streptozotocin (STZ)-induced animal model of Alzheimer's disease (AD). METHODS: To induce the animal model of AD, Sprague-Dawley rats were injected into intracerebroventricular (ICV) injection with 1.5 mg/kg of STZ. Rats were divided into three groups as Sham-con group (n = 7), STZ-con group (n = 7) and STZ-exe group (n = 7). Exercise group ran on the treadmill for 30 min/day, 5 days/week during 6 weeks. RESULTS: The results of this study were as follows: First, STZ-exe group was improved on cognitive function when compared to STZ-con group in water maze test. Second, STZ-exe group help reduce the expression level of amyloid-beta (Aß). In addition, Toll-like receptors-4 (TLR4), Nuclear factor-kB (NF-kB), Tumor necrosis factor-α (TNF-α) and Interleukin-1α (IL-1α) level of STZ-exe group was significantly decreased when compared to STZ-con group. CONCLUSION: These results show that treadmill exercise had positive effect on cognitive function and reduced inflammatory response in STZ-induced animal model of AD.

Treadmill exercise represses neuronal cell death and inflammation during Aß-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice.

Alzheimer's disease (AD) is characterized by the deposition of aggregated amyloid-beta (Aß), which triggers a cellular stress response called the unfolded protein response (UPR). The UPR signaling pathway is a cellular defense system for dealing with the accumulation of misfolded proteins but switches to apoptosis when endoplasmic reticulum (ER) stress is prolonged. ER stress is involved in neurodegenerative diseases including AD, but the molecular mechanisms of neuronal apoptosis and inflammation by Aß-induced ER stress to exercise training are not fully understood. Here, we demonstrated that treadmill exercise (TE) prevented PS2 mutation-induced memory impairment and reduced Aß-42 deposition through the inhibition of ß-secretase (BACE-1) and its product, C-99 in cortex and/or hippocampus of aged PS2 mutant mice. We also found that TE down-regulated the expression of GRP78/Bip and PDI proteins and inhibited activation of PERK, eIF2α, ATF6α, sXBP1 and JNK-p38 MAPK as well as activation of CHOP, caspase-12 and caspase-3. Moreover, TE up-regulated the expression of Bcl-2 and down-regulated the expressions of Bax in the hippocampus of aged PS2 mutant mice. Finally, the generation of TNFα and IL-1α and the number of TUNEL-positive cells in the hippocampus of aged PS2 mutant mice was also prevented or decreased by TE. These results showed that TE suppressed the activation of UPR signaling pathways as well as inhibited the apoptotic pathways of the UPR and inflammatory response following Aß-induced ER stress. Thus, therapeutic strategies that modulate Aß-induced ER stress through TE could represent a promising approach for the prevention or treatment of AD.

Neuroprotective effects of treadmill exercise on BDNF and PI3-K/Akt signaling pathway in the cortex of transgenic mice model of Alzheimer's disease.

(AD). Although physical exercise and AD have received attention in the scientific literature, the mechanism through which treadmill exercise may impact the brain insulin signaling of AD has not been elucidated. This study aimed to evaluate the neuroprotective effects of treadmill exercise on apoptotic factors (Bcl-2/Bax ratio, caspase-3), HSP70, COX-2, BDNF and PI3-K/Akt signaling pathway in the cortex of NSE/hPS2m transgenic mice model of AD. Treadmill exercise ameliorated cognitive function in water maze test and significantly increased the level of Bcl-2/Bax ratio and HSP-70 in Tg-exe group compared to Tg-con group; on the other hand, it significantly decreased the expression of caspase-3 and COX-2 in Tg-exe group compared to Tg-con group. In addition, treadmill exercise significantly increased the expression of BDNF and PI3K/Akt in Tg-exe group compared to Tg-con group. Consequently, treadmill exercise improves cognitive function possibly via activating neurotrophic factor, BDNF and PI3k/Akt signaling pathway, and Aß-induced neuronal cell death in the cortex of Tg mice was markedly suppressed following treadmill exercise. These results suggest that treadmill exercise may be beneficial in preventing or treating Alzheimer's disease.

Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer's disease.

The present study was undertaken to further investigate the protective effect of treadmill exercise on the hippocampal proteins associated with neuronal cell death in an aged transgenic (Tg) mice with Alzheimer's disease (AD). To address this, Tg mouse model of AD, Tg-NSE/PS2m, which expresses human mutant PS2 in the brain, was chosen. Animals were subjected to treadmill exercise for 12 weeks from 24 months of age. The exercised mice were treadmill run at speed of 12 m/min, 60 min/day, 5 days/week on a 0% gradient for 3 months. Treadmill exercised mice improved cognitive function in water maze test. Treadmill exercised mice significantly reduced the expression of Aß-42, Cox-2, and caspase-3 in the hippocampus. In parallel, treadmill exercised Tg mice decreased the phosphorylation levels of JNK, p38MAPK and tau (Ser404, Ser202, Thr231), and increased the phosphorylation levels of ERK, PI3K, Akt and GSK-3α/ß. In addition, treadmill exercised Tg mice up-regulated the expressions of NGF, BDNF and phospho-CREB, and the expressions of SOD-1, SOD-2 and HSP-70. Treadmill exercised Tg mice up-regulated the expression of Bcl-2, and down-regulated the expressions of cytochrome c and Bax in the hippocampus. The number of TUNEL-positive cells in the hippocampus in mice was significantly decreased after treadmill exercise. Finally, serum TC, insulin, glucose, and corticosterone levels were significantly decreased in the Tg mice after treadmill exercise. As a consequence of such change, Aß-dependent neuronal cell death in the hippocampus of Tg mice was markedly suppressed following treadmill exercise. These results strongly suggest that treadmill exercise provides a therapeutic potential to inhibit both Aß-42 and neuronal death pathways. Therefore, treadmill exercise may be beneficial in prevention or treatment of AD.

Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer's disease in an NSE/APPsw-transgenic model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease for which there are few therapeutic regimens that influence the underlying pathogenic phenotypes. However, of the currently available therapies, exercise training is considered to be one of the best candidates for amelioration of the pathological phenotypes of AD. Therefore, we directly investigated exercise training to determine whether it was able to ameliorate the molecular pathogenic phenotypes in the brain using a neuron-specific enolase (NSE)/Swedish mutation of amyloid precursor protein (APPsw) transgenic (Tg) mice as a novel AD model. To accomplish this, Non-Tg and NSE/ APPsw Tg mice were subjected to exercise on a treadmill for 16 weeks, after which their brains were evaluated to determine whether any changes in the pathological phenotype-related factors had occurred. The results indicated (i) that amyloid beta-42 (Abeta-42) peptides were significantly decreased in the NSE/APPsw Tg mice following exercise training; (ii) that exercise training inhibited the apoptotic biochemical cascades, including cytochrome c, caspase-9, caspase-3 and Bax; (iii) that the glucose transporter-1 (GLUT-1) and brain-derived neurotrophic factor (BDNF) proteins induced by exercise training protected the neurons from injury by inducing the concomitant expression of genes that encode proteins such as superoxide dismutase-1 (SOD-1), catalase and Bcl-2, which suppress oxidative stress and excitotoxic injury; (iv) that heat-shock protein-70 (HSP-70) and glucose-regulated protein-78 (GRP-78) were significantly increased in the exercise (EXE) group when compared to the sedentary (SED) group, and that these proteins may benefit the brain by making it more resistant to stress-induced neuron cell damage; (v) and that exercise training contributed to the restoration of normal levels of serum total cholesterol, insulin and glucose. Taken together, these results suggest that exercise training represents a practical therapeutic strategy for human subjects suffering from AD. Moreover, this training has the potential for use in new therapeutic strategies for the treatment of other chronic disease including diabetes, cardiovascular and Parkinson's disease.