title: Treadmill exercise represses neuronal cell death and inflammation during Aβ-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice.
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.
authors.affiliation: Exercise Biochemistry Laboratory, Korea National Sport University, 88-15 Oryun-dong, Songpa-gu, Seoul, 138-763, Korea.
authors.forename: Eun-Bum
authors.initials: EB
authors.lastname: Kang
authors.affiliation: Exercise Biochemistry Laboratory, Korea National Sport University, 88-15 Oryun-dong, Songpa-gu, Seoul, 138-763, Korea.
authors.forename: In-Su
authors.initials: IS
authors.lastname: Kwon
authors.affiliation: Exercise Biochemistry Laboratory, Korea National Sport University, 88-15 Oryun-dong, Songpa-gu, Seoul, 138-763, Korea.
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Koo
authors.affiliation: Department of Physical Education, Kyonggi University, 94-6 Yiui-Dong Yeongtong-Gu, Gyeonggi-Do, Suwon, 443-760, Korea.
authors.forename: Eung-Joon
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Exercise Biochemistry Laboratory, Korea National Sport University, 88-15 Oryun-dong, Songpa-gu, Seoul, 138-763, Korea.
authors.forename: Chul-Hyun
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, Han-Yang University, Seoul, 133-791, Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Aviation and Marine Sports, University of Han-Seo, Seosansi, 306-706, Korea.
authors.forename: Choon-Ho
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Exercise Biochemistry Laboratory, University of West Florida, 11000 University Pkwy, Bldg. 72, Pensacola, FL, 32514, USA.
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Lee
authors.affiliation: Exercise Biochemistry Laboratory, Korea National Sport University, 88-15 Oryun-dong, Songpa-gu, Seoul, 138-763, Korea.
authors.forename: In-Ho
authors.initials: IH
authors.lastname: Cho
authors.affiliation: Exercise Biochemistry Laboratory, Korea National Sport University, 88-15 Oryun-dong, Songpa-gu, Seoul, 138-763, Korea. chojy86@knsu.ac.kr.
authors.forename: Joon-Yong
authors.initials: JY
authors.lastname: Cho
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000517:prevention & control*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D010805:Physical Conditioning, Animal; D053766:Presenilin-2 / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D010446:Peptide Fragments; D053766:Presenilin-2; D019253:Proto-Oncogene Proteins c-bcl-2; C095101:Psen2 protein, mouse; C075222:amyloid beta-protein (1-42); D020928:Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D020169:Caspases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse