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J. Biol. Chem., Vol. 278, Issue 50, 49819-49827, December 12, 2003

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

Ka-Chun Suen, Man-Shan Yu, Kwok-Fai So, Raymond Chuen-Chung Chang, and Jacques Hugon

From the Laboratory of Neurodegenerative Diseases, Department of Anatomy, Faculty of Medicine, and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong

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 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 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.

Received for publication, June 19, 2003 , and in revised form, September 2, 2003.

^* This work was supported in part by Hong Kong Research Grant Council (HKU 7305/00 M) (to J. H.) and by HKU Seed Funding for Basic Research (2001–2002 and 2002–2003) (to R. C.-C. C.) and is a part of Area of Excellence (AOE/P-10/01). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Dept. of Anatomy, Faculty of Medicine, Laboratory Block, Faculty of Medicine Bldg., The University of Hong Kong, 21 Sassoon Rd., Pokfulam, Hong Kong. Tel.: 852-2819-9127; Fax: 852-2817-0857; E-mail: rccchang{at}hkucc.hku.hk. To whom correspondence may be addressed: Service de Neurologie, CHU de Poitiers, Poitiers 86021, France. Tel.: 33-5-49-44-4446; Fax: 33-5-49-44-4851; E-mail: j.hugon{at}chu-poitiers.fr.

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