GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases.
Glial cell line-derived neurotrophic factor (GDNF) is a potent survival agent for neurons, however, its effect on A beta-evoked neuronal death has not been examined. We show that the injection of A beta into New Zealand white rabbit brain activates the endoplasmic reticulum (ER) chaperones, grp 78 and grp 94, and the transcription factor, gadd 153. These effects correlate with the activation of JNK and ERK as well as of microglia and with the phosphorylation of tau protein. Treatment with GDNF inhibits the activation of gadd 153, reduces the phosphorylation of JNK, abolishes the phosphorylation of ERK, prevents microglial activation, greatly reduces apoptotic cells, and does not affect the phosphorylation of tau. Our data suggest that the tau hyperphosphorylation and apoptosis triggered by A beta are two independent events, and that the neuroprotective effect of GDNF against A beta may result either directly by the inhibition of ER stress or indirectly through the inhibition of JNK and ERK activation.
Ghribi
Othman
O
Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA. og2p@virginia.edu
Herman
Mary M
MM
Pramoonjago
Patcharin
P
Spaulding
Natalie K
NK
Savory
John
J
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D022762:CCAAT-Enhancer-Binding Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D051742:Transcription Factor CHOP; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases