GDNF regulates the Aβ-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 Abeta-evoked neuronal death has not been examined. We show that the injection of Abeta 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 Abeta are two independent events, and that the neuroprotective effect of GDNF against Abeta may result either directly by the inhibition of ER stress or indirectly through the inhibition of JNK and ERK activation. (C) 2004 Elsevier Inc. All rights reserved.