Elsevier

Neuroscience Research

Volume 69, Issue 2, February 2011, Pages 161-173
Neuroscience Research

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

https://doi.org/10.1016/j.neures.2010.10.004Get rights and content

Abstract

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 Aβ-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/β. 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, Aβ-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 Aβ-42 and neuronal death pathways. Therefore, treadmill exercise may be beneficial in prevention or treatment of AD.

Research highlights

▶ Treadmill exercise ameliorates cognitive deficits in Tg mice. ▶ Treadmill exercise reduces Aβ-42 and tau deposition in Tg mice. ▶ Treadmill exercise reduces the number of TUNEL-positive cells in Tg mice. ▶ Treadmill exercise reduces TC, insulin, glucose, and corticosterone levels in Tg mice. ▶ Treadmill exercise may be beneficial in prevention or treatment in AD.

Introduction

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by co-existence of neuritic plaque and neurofibrillary tangles (NFT) associated with neuronal cell death in the brain. Although late-onset or sporadic AD is as yet unknown, mutations of amyloid precursor protein (APP) and presenilin (PS) genes linked to familial Alzheimer's disease (FAD) induce neuronal cell death, possibly via β-amyloid-42 (Aβ-42) deposition (Tabira et al., 2002, Hwang et al., 2002). Although multiple mechanisms for Aβ-induced neuronal cell death have been hypothesized including effects on tau phosphorylation, there is considerable evidence implicating a role for Aβ-induced disruption of kinases and proteins critical for neuronal cell death (Niikura et al., 2002, Huang and Jiang, 2009).

Aβ-dependent neuronal cell death involves potential signaling events including mitogen-activated protein kinase (MAPK) pathway (Daniels et al., 2001, Savage et al., 2002, Munoz and Ammit, 2010), phosphatidylinositol 3-kinases (PI3K)-Akt-glycogen synthases kinases-3 (GSK-3) signaling pathway (Jolivalt et al., 2008, Takashima, 2006, Cole and Frautschy, 2007) and caspase-dependent pathway (Gervais et al., 1999, Awasthi et al., 2005, Um et al., 2008), indicating that these pathways contribute either directly or indirectly, to Aβ-dependent neuronal cell death or brain function, in AD Tg mice and patients.

In addition, Aβ neurotoxicity has been shown to elevate the expression of neuronal cyclooxygenase-2 (Cox-2), indicating that neuronal Cox-2 may contribute to the pathology of AD by promoting cognitive deficits and apoptotic neuronal cell deaths, which are regulated by MAPK phosphorylation (Yasojima et al., 1999, Hwang et al., 2002). In contrast, several neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and cAMP-response element binding protein (CREB) have been identified that they may prevent neuronal cell death and stimulate survival and function of neuron cells in the AD brains (Holtzman and Mobley, 1994, Bourtchuladze et al., 1994, Korte et al., 1995, Lonze and Ginty, 2002, Peng et al., 2009).

Taken together, any or all of the above mentioned proteins are potential trigger for the neuronal cell death and survival. Therefore, studies investigating death and survival of neuronal cells exposed to AD insults would be a step in the search for therapy leading to recovery from AD and elucidation of molecular mechanism responsible for the effect of therapeutic interventions to repress neuronal cell death in AD is current, extensive research focus. A large number of epidemiological studies have suggested a possible protective effect of physical exercise, pharmaceutical and nutriceutical compounds with AD (Cho et al., 2003, Cho et al., 2010, Aisen, 2005, Cotman et al., 2007).

Recently, benefits of physical exercise as a non-pharmacological approach in the management of patients with AD have been highlighted. One of the major clues is the fact that transition from a sedentary life-style to a simple active life-style may be sufficient to repress neuronal cell death in both animal models and patients of AD, indicating that physical activity or active life might protect against AD (Cotman and Berchtold, 2002, Fratiglioni et al., 2004). Although this common perception is supported by epidemiological studies, and persons performing regular physical exercise or leading active life style have a decreased risk of developing AD, the biological and molecular basis for such benefits remains elusive.

In the present study, the Tg-NSE/hPS2m mouse model of AD was used to directly test the hypothesis that treadmill exercise can alleviate cognitive impairment in the Morris water maze test and reduce the Aβ-42 and the tau phosphorylation levels, possibly via a number of potential signaling events including the MAPK pathway, PI3-K/Akt/GSK-3 signaling pathway, and the caspase-dependent pathway in AD.

Furthermore, we have sought to determine if treadmill exercise reduces the expressions of Cox-2, caspase-3 and proapoptotic proteins (cytochrome c and Bax) and increases the expressions of Bcl-2 and antioxidant enzymes such as superoxide dismutase-1 (SOD-1) and superoxide dismutase-2 (SOD-2) with molecular chaperone, heat shock protein-70 (HSP-70) and neurotrophic factors such as NGF, BDNF and CREB, and if it contributes to reduction in the presence of TUNEL-positive cells and restoration of normal levels of serum total cholesterol, glucose, insulin, and corticosterone in Tg-NSE/hPS2m mice. Therefore, the purpose of this study was to evaluate the effects of treadmill exercise on neuronal cell death in brain with AD model mice.

Section snippets

Transgenic mice

All animal experimental procedures used in this study were approved by the Institutional Animal Care and Use Committee at Korea National Sport University and by the Korea FDA. Transgenic mice, Tg-NSE/hPS2m, expressing human PS2 mutant under the control of neuron-specific enolase (NSE) were maintained in the genetic background of C57BL/6 × DBA/2 mice, as described previously (Hwang et al., 2002). The mice were maintained under a 12:12 h dark–light cycle, housed at 22 ± 2 °C with 50% relative humidity,

Treadmill exercise ameliorates cognitive deficit in Tg-NSE/hPS2m mice

The two-way ANOVA on escape distances data (Fig. 1A-a) indicated significant effects for group [F(1,28) = 8.72, p < .01], exercise condition [F(1,28) = 17.38, p < .001], but revealed no significant group by exercise condition interaction. The two-way ANOVA on escape velocities data (Fig. 1A-b) indicated significant effects for group [F(1,28) = 5.81, p < .05], exercise condition [F(1,28) = 14.52, p < .01], but revealed no significant group by exercise condition interaction. The two-way ANOVA on escape latencies

Discussion

In our study, we found that treadmill exercise reduced Aβ-42 deposition in the hippocampus of Tg-NSE/PS2m mice. This reduction was compatible with the effects seen with treadmill exercise such as Aβ immunization, which resulted in a significant reduction in Aβ in these same transgenic mice (Cho et al., 2003). This effect may involve neuronal metabolism changes that are known to affect proteolytic processing of amyloid precursor protein (APP) and to be regulated by exercise training. Then, this

Acknowledgements

We thank the animal technicians Kwang-O. Shin, Ju-C. Park and Seoung-H. Wang. In addition, we thank Jang-S. Yook for directing the animal facility at the Korea National Sport University. This study was supported by grants to Professor Joon-Y. Cho from the National Research Foundation G00036 (I02282).

References (53)

  • O. Lazarov et al.

    Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice

    Cell

    (2005)
  • B.E. Lonze et al.

    Function and regulation of CREB family transcription factors in the nervous system

    Neuron

    (2002)
  • M.P. Mattson et al.

    Prophylactic activation of neuroprotective stress response pathways by dietary and behavioral manipulations

    NeuroRx

    (2004)
  • L. Munoz et al.

    Targeting p38 MAPK pathway for the treatment of Alzheimer's disease

    Neuropharmacology

    (2010)
  • E. Narath et al.

    Voluntary and forced exercise influence the survival and body composition of ageing male rats differently

    Exp. Gerontol.

    (2001)
  • A. Parachikova et al.

    Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition

    Neurobiol. Dis.

    (2008)
  • J.D. Sweatt

    Mitogen-activated protein kinases in synaptic plasticity and memory

    Curr. Opin. Neurobiol.

    (2004)
  • S. Willaime-Morawek et al.

    C-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

    Neuroscience

    (2003)
  • S.P. Yang et al.

    Co-accumulation of vascular endothelial growth factor with beta-amyloid in the brain of patients with Alzheimer's

    Neurobiol. Aging

    (2004)
  • S. Yanagita et al.

    Effects of spontaneous and forced running on activation of hypothalamic corticotropin-releasing hormone neurons in rats

    Life Sci.

    (2007)
  • K. Yasojima et al.

    Distribution of the cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs

    Brain Res.

    (1999)
  • C.M. Yuede et al.

    Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 mouse model of Alzheimer's disease

    Neurobiol. Dis.

    (2009)
  • P.A. Adlard et al.

    Voluntary exercise decreases amyloid load in transgenic model of Alzheimer's disease

    J. Neurosci.

    (2005)
  • P.S. Aisen

    Pharmacologic treatment options in Alzheimer's disease: optimizing disease management

    J. Am. Acad. Nurse Pract.

    (2005)
  • J. Campisi et al.

    Habitual physical activity facilitates stress-induced HSP72 induction in brain, peripheral, and immune tissues

    Am. J. Physiol. Regul. Integr. Comp. Physiol.

    (2003)
  • M. Chennaoui et al.

    Effects of moderate and intensive training on the hypothalamo–pituitary–adrenal axis in rats

    Acta Physiol. Scand.

    (2002)
  • Cited by (0)

    View full text