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

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Abstract

Alzheimer’s disease (AD) is characterized by the deposition of aggregated amyloid-beta (Aβ), 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 Aβ-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 Aβ-42 deposition through the inhibition of β-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 Aβ-induced ER stress. Thus, therapeutic strategies that modulate Aβ-induced ER stress through TE could represent a promising approach for the prevention or treatment of AD.

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Acknowledgments

We thank the animal technicians Yo-W Choi, Dong-H Choi, and Seok-M, Hong for directing the animal facility at Korea National Sport University. This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (NRF-2011-013-G00016).

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Authors and Affiliations

  1. Exercise Biochemistry Laboratory, Korea National Sport University, 88-15 Oryun-dong, Songpa-gu, Seoul, 138-763, Korea

    Eun-Bum Kang, In-Su Kwon, Jung-Hoon Koo, Chul-Hyun Kim, In-Ho Cho & Joon-Yong Cho

  2. Department of Anatomy and Cell Biology, College of Medicine, Han-Yang University, Seoul, 133-791, Korea

    Jin Lee

  3. Exercise Biochemistry Laboratory, University of West Florida, 11000 University Pkwy, Bldg. 72, Pensacola, FL, 32514, USA

    Young-Il Lee

  4. Department of Physical Education, Kyonggi University, 94-6 Yiui-Dong Yeongtong-Gu, Gyeonggi-Do, Suwon, 443-760, Korea

    Eung-Joon Kim

  5. Department of Aviation and Marine Sports, University of Han-Seo, Seosansi, 306-706, Korea

    Choon-Ho Yang

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  1. Eun-Bum Kang
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Kang, EB., Kwon, IS., Koo, JH. et al. Treadmill exercise represses neuronal cell death and inflammation during Aβ-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice. Apoptosis 18, 1332–1347 (2013). https://doi.org/10.1007/s10495-013-0884-9

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  • DOI: https://doi.org/10.1007/s10495-013-0884-9

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