Amyloid beta-peptide 31-35-induced neuronal apoptosis is mediated by caspase-dependent pathways via cAMP-dependent protein kinase A activation |
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Authors: | Zhao Li Qian Zhong-Ming Zhang Ce Wing Ho Yung Du Fang Ya Ke |
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Affiliation: | Department of Sports Physiology, Beijing Sport University, Beijing 100084, China; Department of Neurobiology, Shanxi Medical University, Taiyuan, PRC 030001; Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong; Department of Applied Biology &Chemical Technology, and National Key Laboratory of Chinese Medicine and Molecular Pharmacology (Shenzhen), Hong Kong Polytechnic University, Kowloon, Hong Kong |
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Abstract: | This study aims to investigate the roles of the protein kinase A (PKA)- and caspase-dependent pathways in amyloid beta-peptide 31-35 (Abeta[31-35])-induced apoptosis, and the mechanisms of neuroprotection by group III metabotropic glutamate receptor (mGluR) activation against apoptosis induced by Abeta[31-35] in cortical neurons. We demonstrated that Abeta[31-35] induces neuronal apoptosis as well as a significant increase in caspase-3, -8 and -9. Activation of group III mGluRs by l-serine-O-phosphate and (R,S)-4-phosphonophenylglycine (two group III mGluR agonists), which attenuate the effects of Abeta[31-35], provides neuroprotection to the cortical neurons subjected to Abeta[31-35]. We also showed that Rp-cAMP, an inhibitor of cAMP-dependent PKA, has the ability to protect neurons from Abeta[31-35]-induced apoptosis and to reverse almost completely the effects of Abeta[31-35] on the activities of caspase-3. Further, we found that Sp-cAMP, an activator of cAMP-dependent PKA, can significantly abolish the l-serine-O-phosphate- and (R,S)-4-phosphonophenylglycine-induced neuroprotection against apoptosis, and decrease caspase-3, -8 and -9 in the Abeta[31-35]-treated neurons. Our findings suggest that neuronal apoptosis induced by Abeta[31-35] is mediated by the PKA-dependent pathway as well as the caspase-dependent intrinsic and extrinsic apoptotic pathways. Activation of group III mGluRs protects neurons from Abeta[31-35]-induced apoptosis by blocking the caspase-dependent pathways. Inhibition of the PKA-dependent pathway might also protect neurons from Abeta[31-35]-induced apoptosis by blocking the caspase-dependent pathways. Taken together, our observations suggest that Abeta[31-35] might have the ability to activate PKA, which in turn activates the caspase-dependent intrinsic and extrinsic apoptotic pathways, inducing apoptosis in the cortical neurons. |
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Keywords: | amyloid β-peptide 31–35 (Aβ[31–35]) apoptosis cortical neurons group III metabotropic glutamate receptors (mGluRs) neuroprotection caspase-dependent intrinsic and extrinsic pathways PKA-dependent pathway |
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