期刊
APOPTOSIS
卷 18, 期 11, 页码 1332-1347出版社
SPRINGER
DOI: 10.1007/s10495-013-0884-9
关键词
Alzheimer's disease; Endoplasmic reticulum stress; Unfolded protein response; Neuroinflammation; Neuronal cell death; Treadmill exercise
资金
- National Research Foundation of Korea
- Korean Government [NRF-2011-013-G00016]
Alzheimer's disease (AD) is characterized by the deposition of aggregated amyloid-beta (A beta), 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 A beta-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 A beta-42 deposition through the inhibition of beta-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, eIF2 alpha, ATF6 alpha, 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 TNF alpha and IL-1 alpha 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 A beta-induced ER stress. Thus, therapeutic strategies that modulate A beta-induced ER stress through TE could represent a promising approach for the prevention or treatment of AD.
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