Amyloid beta-peptide 31-35-induced neuronal apoptosis is mediated by caspase-dependent pathways via cAMP-dependent protein kinase A activation

Aging Cell. 2008 Jan;7(1):47-57. doi: 10.1111/j.1474-9726.2007.00352.x. Epub 2007 Dec 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Apoptosis / drug effects*
  • Caspase 3 / metabolism
  • Caspase 8 / metabolism
  • Caspase 9 / metabolism
  • Caspases / metabolism*
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • In Situ Nick-End Labeling
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Peptide Fragments / toxicity*
  • Phosphoserine / pharmacology
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Signal Transduction


  • 4-phosphonophenylglycine
  • Amyloid beta-Peptides
  • Peptide Fragments
  • Protein Kinase Inhibitors
  • Receptors, Metabotropic Glutamate
  • amyloid beta-protein (31-35)
  • metabotropic glutamate receptor 3
  • Phosphoserine
  • Cyclic AMP-Dependent Protein Kinases
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases
  • Glycine