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.