One of the hallmarks of Alzheimer's disease is extracellular accumulation of senile plaques composed primarily of aggregated ␤-amyloid (A␤) peptide. Treatment of cultured neurons with A␤ peptide induces neuronal death in which apoptosis is suggested to be one of the mechanisms. We have demonstrated previously that A␤ peptide induces activation of double-stranded RNA-dependent serine/threonine protein kinase (PKR) and phosphorylation of eukaryotic initiation factor 2␣ (eIF2␣) in neurons in vitro. Degenerating neurons in brain tissues from Alzheimer's disease patients also displayed high immunoreactivity for phosphorylated PKR and eIF2␣. Our previous data have also indicated that PKR plays a significant role in mediating A␤ peptideinduced 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 A␤ peptide toxicity. Therefore, it is important to understand how PKR is activated by A␤ peptide. We report here that inhibition of caspase-3 activity reduces phosphorylation of PKR and to a certain extent, cleavage of PKR and eIF2␣ in neurons exposed to A␤ 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 A␤ 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 A␤ peptide exposure. Elucidation of the upstream pathways for PKR activation can help us to understand how this kinase participates in A␤ peptide neurotoxicity and to develop effective neuroprotective strategy.

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. (2003) Reduction of calcium release from the endoplasmic reticulum could only provide partial neuroprotection against betaamyloid peptide toxicity.