Amyloid beta-peptide 31-35-induced neuronal apoptosis is mediated by caspase-dependent pathways via cAMP-dependent protein kinase A activation.
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.
Zhao
Li
L
Department of Sports Physiology, Beijing Sport University, Beijing 100084, China.
Qian
Zhong-Ming
ZM
Zhang
Ce
C
Wing
Ho Yung
HY
Du
Fang
F
Ya
Ke
K
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D010768:Phosphoserine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D015398:Signal Transduction
C119327:4-phosphonophenylglycine; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D018094:Receptors, Metabotropic Glutamate; C113042:amyloid beta-protein (31-35); C102718:metabotropic glutamate receptor 3; D010768:Phosphoserine; D017868:Cyclic AMP-Dependent Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D005998:Glycine