Erythropoietin protects PC12 cells from beta-amyloid(25-35)-induced apoptosis via PI3K/Akt signaling pathway.
Although the etiology of Alzheimer's disease (AD) is not fully understood, multiple lines of evidence suggests the importance of amyloid-beta (Abeta) in the initiation/progression of the disease. In this study, we investigated protective effects of erythropoietin (EPO) on Abeta(25-35)-induced cell death in cultured rat pheochromocytoma cells (PC12 cells). EPO (2U/ml) in combination with Abeta(25-35) increased the cell viability and reduced the number of apoptotic cells by MTT assay, Trypan blue dye exclusion method, TUNEL staining and Hoechst 33342 staining. In mechanistic study, EPO induced time-dependent phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. Treatment of PC12 cells with PI3K inhibitors LY294002 abolished the protective effects of EPO. EPO also induced the phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), a downstream target of PI3K/Akt, and GSK-3beta inhibitors lithium chloride blocked Abeta(25-35)-induced cell apoptosis in a manner similar to EPO, suggesting that GSK-3beta inhibition is involved in EPO-mediated cytoprotection. Moreover, the expression of anti-apoptotic protein Bcl-2 was increased by EPO involving PI3K/Akt pathway. These studies demonstrate that EPO is an effective neuroprotective agent and is a viable candidate for treating AD.
Ma
Rong
R
Department of Pharmacology, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China.
Xiong
Nian
N
Huang
Chengfang
C
Tang
Qiang
Q
Hu
Benrong
B
Xiang
Jizhou
J
Li
Gang
G
D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C074636:amyloid beta-protein (25-35); D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3