title: Moderate activation of autophagy regulates the intracellular calcium ion concentration and mitochondrial membrane potential in beta-amyloid-treated PC12 cells.
abstract: Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disease. Aggregated beta-amyloid (Aβ) disturbs Ca(2+) homeostasis and causes mitochondrial dysfunction and finally underlies AD. Recent evidence suggests that autophagy initiation by Beclin-1 protein might be involved in the pathogenesis of AD. However, the effects of Beclin-1 dependent autophagy on intracellular calcium ion concentration ([Ca(2+)]i) and mitochondrial membrane potential (MMP) is unclear. The effects of Beclin-1 dependent autophagy that were activated by a gradient concentration of autophagy activator rapamycin or inhibited by autophagy inhibitor 3-methyladenine (3-MA) on cell viability and cell morphology were examined. Pretreatment with rapamycin significantly up-regulated the expression of Beclin-1 in response to Aβ1-42 application, but after pretreatment with 3-MA it was significantly down-regulated. Moderate activation of Beclin-1 dependent autophagy had an up regulation effect on cell viability and could maintain the original morphology of cells. Furthermore, rapamycin or 3-MA on [Ca(2+)]i and MMP in Aβ1-42 treatment of PC12 cells were evaluated. We also report that PC12 cells treated with Aβ1-42 showed an increase in [Ca(2+)]i but a decrease in MMP when compared to the normal control. However the application of rapamycin prior to this prevented the increase in [Ca(2+)]i and the decrease in MMP in response to Aβ1-42. When 3-MA was applied this exacerbated the effect of Aβ1-42 on the [Ca(2+)]i and the MMP. This shows that moderate activation of Beclin-1 dependent autophagy by rapamycin can modulate Ca(2+) homeostasis and maintain MMP in response to Aβ1-42 induced cytotoxicity and so may have a preventive function in AD.
authors.affiliation: The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Sanya Hospital of Traditional Chinese Medicine, Sanya, China.
authors.forename: Zhongfeng
authors.initials: Z
authors.lastname: Xue
authors.affiliation: The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Hainan Tropical Ocean University, Sanya, China.
authors.forename: Yalei
authors.initials: Y
authors.lastname: Guo
authors.affiliation: The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China. Electronic address: fangyq2@163.com.
authors.forename: Yongqi
authors.initials: Y
authors.lastname: Fang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D042541:Intracellular Space / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D010588:Phagosomes / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C025946:3-methyladenine; D000225:Adenine; D002118:Calcium; D020123:Sirolimus
keywords: Alzheimer’s disease; Autophagy; Beclin-1; Beta-amyloid; Intracellular calcium; Mitochondrial membrane potential