Upstream Signaling Pathways Leading to the Activation of Double-stranded RNA-dependent Serine/Threonine Protein Kinase in β-Amyloid Peptide Neurotoxicity

Abstract

One of the hallmarks of Alzheimer's disease is extracellular accumulation of senile plaques composed primarily of aggregated β-amyloid (Aβ) peptide. Treatment of cultured neurons with Aβ peptide induces neuronal death in which apoptosis is suggested to be one of the mechanisms. We have demonstrated previously that Aβ peptide induces activation of double-stranded RNA-dependent serine/threonine protein kinase (PKR) and phosphorylation of eukaryotic initiation factor 2α (eIF2α) in neurons in vitro. Degenerating neurons in brain tissues from Alzheimer's disease patients also displayed high immunoreactivity for phosphorylated PKR and eIF2α. Our previous data have also indicated that PKR plays a significant role in mediating Aβ peptide-induced neuronal death, because neurons from PKR knockout mice and neuroblastoma SH-SY5Y cells stably transfected with dominant negative mutant of PKR are less susceptible to Aβ peptide toxicity. Therefore, it is important to understand how PKR is activated by Aβ peptide. We report here that inhibition of caspase-3 activity reduces phosphorylation of PKR and to a certain extent, cleavage of PKR and eIF2α in neurons exposed to Aβ peptide. Calcium release from the endoplasmic reticulum and activation of caspase-8 are the upstream signals modulating the caspase-3-mediated activation of PKR by Aβ peptide. Although in other systems HSP90 serves as a repressor for PKR, it is unlikely the candidate for caspase-3 to affect PKR activation in neurons after Aβ peptide exposure. Elucidation of the upstream pathways for PKR activation can help us to understand how this kinase participates in Aβ peptide neurotoxicity and to develop effective neuroprotective strategy.