Molecular signaling of double-stranded RNA-dependent protein kinase (PKR) in beta-amyloid peptide (A beta)-induced neuronal death

Abstract

Accumulation of Ab peptides has been considered to play important roles in thepathogenesis of Alzheimer’s disease (AD). Ab neurotoxicity is mediated via awide array of intracellular signaling pathways including increases in intracellularcalcium, different mitogen activated kinases and caspases. We have recentlyshown that attenuation of intracellular calcium provides significant but partialneuroprotective effect only. While endoplasmic reticulum (ER) stress responsesare not early activated right after exposure to Ab, phosphorylation of eukaryoticinitiation factor 2a (eIF2a) are detected at early time points. The roles of PKR arethus intensively studied from our group. We are the first laboratory to show theinvolvement of PKR in Ab neurotoxicity. PKR not just involves but playssignificant roles in Ab neurotoxicity. Over-expression of negatively mutatedneuroblastoma cells as well as primary cultured neurons from PKR knockout micedemonstrate a marked reduction of neuronal death. Postmortem AD brain sectionsalso elicit high immunoreactivity for phosphorylated PKR and eIF2a. We haverecently shown the upstream pathways for PKR to be activated by Ab. Early andmild activation of caspase-3 can function as signaling molecule mediatingactivation of PKR. Taken together, while PKR is not specific for Ab neurotoxicityand for AD, it will trigger pro-apoptotic signaling cascade in neurons once it isactivated. PKR may become a new potential pharmaceutical target for developingneuroprotective agent.