Protective effects of galantamine against Abeta-induced PC12 cell apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum stress.
Amyloid beta (Abeta) is considered to be responsible for the pathogenesis of Alzheimer's disease (AD). Mitochondrial and ER apoptotic pathways are considered to be involved in this process. Galantamine is an acetylcholinesterase (AChE) inhibitor widely used for patients with AD. In this study, we investigated the neuroprotective effects of galantamine on Abeta(25-35)-induced apoptosis in PC12 cells and the underlying mechanisms. Exposure of PC12 cells to 20 microM Abeta(25-35) caused significant cell viability loss and apoptosis, Abeta aggregation, mitochondrial and ER morphological changes, as well as mitochondrial membrane potential dissipation, reactive oxygen species (ROS) production, intracellular calcium elevation, and cytochrome c release from mitochondria. Pretreatment with 10 microM galantamine for 24 h prior to Abeta(25-35) exposure significantly reduced Abeta(25-35)-induced apoptosis not only by preventing Abeta aggregation, mitochondrial and ER morphological changes, mitochondrial membrane potential dissipation, ROS production, intracellular calcium elevation, and cytochrome c release, but also via reversing Bcl-2/Bax ratio and suppressing the activity of GADD153, Grp78/94, caspase-9, caspase-12, and caspase-3. All these data indicate that galantamine protects PC12 cells against Abeta(25-35)-induced apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum (ER) stress.
Liu
Xiaoyu
X
Department of Biomedical Engineering, Zhejiang University, Key Laboratory of Biomedical Engineering of Ministry of Education, Hangzhou, Zhejiang, China.
Xu
Kedi
K
Yan
Ming
M
Wang
Yongping
Y
Zheng
Xiaoxiang
X
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001562:Benzimidazoles; D052160:Benzothiazoles; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D003224:Congo Red; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000648:ultrastructure; D005456:Fluorescent Dyes; D005702:Galantamine / Q000494:pharmacology*; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D018696:Neuroprotective Agents; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D001562:Benzimidazoles; D052160:Benzothiazoles; D004396:Coloring Agents; D005456:Fluorescent Dyes; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D013844:Thiazoles; C074636:amyloid beta-protein (25-35); D005702:Galantamine; C009462:thioflavin T; D003224:Congo Red; D045304:Cytochromes c; C017807:bisbenzimide ethoxide trihydrochloride; D002118:Calcium