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

Exercise Biochemistry Laboratory, Korea National Sport University, Seoul 138-763, Korea.
International Journal of Molecular Medicine (Impact Factor: 2.09). 11/2008; 22(4):529-39. DOI: 10.3892/ijmm_00000052
Source: PubMed


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.

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Available from: Yea-Hyun Leem, May 09, 2014
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    • "No change in GLUT4 expression and a significant increase in GLUT2 protein levels, proposed to be caused by astrocyte activation, were found in the brain of AD patients by Bigl et al. (2003) while both decreased and unaltered expression of GLUT2 mRNA was found in basal forebrain neurons in the late stage of AD (Counts et al., 2009). Unaltered GLUT4 (Lee et al., 2013) and decreased GLUT1 and GLUT3 protein expression was found also in transgenic mice models of AD (Kouznetsova et al., 2006; Hoojimans et al., 2007; Um et al., 2008; Lee et al., 2013) while no such data have been reported in STZ-icv sAD model. It is logical to assume that impaired insulin receptor signaling in the brain such as that observed in human sAD and its animal counterpart, STZ-icv rat model, is accompanied by decreased insulin-dependent glucose transport in the brain. "
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    ABSTRACT: Basic and clinical research has demonstrated that dementia of sporadic Alzheimer's disease (sAD) type is associated with dysfunction of the insulin-receptor (IR) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells. An alternative source of energy is D-galactose (the C-4-epimer of D-glucose) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway. Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral galactose treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral galactose (200 mg/kg/day) treatment on cognitive deficits in streptozotocin-induced (STZ-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral galactose treatment initiated immediately after the STZ-icv administration, successfully prevented development of the STZ-icv-induced cognitive deficits. Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg/kg/day. Additionally, oral galactose administration led to the appearance of galactose in the blood. The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose. Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of cognitive deficits associated with glucose hypometabolism in AD.
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    • "Moreover, because the hippocampus of AD animals maintains the capacity for cellular plasticity, potentiating neurogenesis has been considered as a potential therapy to delay AD progression (Mu and Gage, 2011). Positive regulators of neurogenesis, such as exposure to an enriched environment or physical exercise, improve cognitive performance and reduce amyloid deposition in transgenic mouse models of familial AD (Adlard et al., 2005; Maesako et al., 2012; Um et al., 2008; Yuede et al., 2009). Prolonged voluntary exercise improved spatial memory, enhanced hippocampal neurogenesis and increased brain-derived neurotrophic factor (BDNF) levels in middle-aged wild-type mice (Marlatt et al., 2012) and in APP/PS1 transgenic mice (Liu et al., 2011). "
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    • "ed aerobic exercise in an animal model of HPA and found that regular exercise prevents the decreased antioxi - dant enzyme activities and lipid peroxidation caused by HPA . Regular exercise has been proven to act as a neuroprotective factor in neurodegenerative diseases that involve oxidative stress in their physiopathology ( Dibble et al . 2009 ; Um et al . 2008 ) . Each exercise session normally increases reactive species due to increased metabolic de - mand which emphasizes the prospect of exercising with antioxidant supplementation , since the stress caused by each exercise session can effectively increase the antioxidant de - fenses ( Halliwell 2011 ) . Furthermore , alpha - tocopherol has "
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