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Swedish amyloid precursor protein mutation increases phosphorylation of eIF2alpha in vitro and in vivo

Cited 28 time in Web of Science Cited 26 time in Scopus
Authors
Kim, Hye-Sun; Choi, Yoori; Shin, Ki-Young; Joo, Yuyoung; Lee, Yong-Kyu; Jung, Sang Yong; Suh, Yoo-Hun; Kim, Joung-Hun
Issue Date
2007
Publisher
Wiley-Blackwell
Citation
J Neurosci Res 85:1528-1537
Keywords
Alzheimer Disease/*metabolismAmyloid beta-Protein Precursor/genetics/*metabolismAnimalsCase-Control StudiesCell Death/physiologyCell LineCerebral Cortex/cytology/*metabolismEukaryotic Initiation Factor-2/*metabolismGene Expression Regulation/physiologyHumansImmunohistochemistryMatched-Pair AnalysisMiceMice, TransgenicMutationNeurons/*metabolismPhosphorylationRatsRats, Sprague-DawleyReactive Oxygen Species/*metabolismTransfectionVitamin E/metabolism
Abstract
Swedish double mutation (KM670/671NL) of amyloid precursor protein (Swe-APP), a prevailing cause of familial Alzheimer's disease (FAD), is known to increase in Abeta production both in vitro and in vivo, but its underlying molecular basis leading to Alzheimer's disease (AD) pathogenesis remains to be elucidated, especially for the early phase of disease. We have confirmed initially that the expression of Swe-APP mutant transgene reduced cell viability via ROS production but this effect was eliminated by an anti-oxidative agent, vitamin E. We also found that eukaryotic translation initiation factor-2alpha (eIF2alpha), which facilitates binding of initiator tRNA to ribosomes to set on protein synthesis, was phosphorylated in cultured cells expressing Swe-APP. This increase in phosphorylated eIF2alpha was also attenuated significantly by treatment with vitamin E. The finding that eIF2alpha became highly phosphorylated by increased production of Abeta was substantiated in brain tissues of both an AD animal model and AD patients. Although an increase in Abeta production would result in cell death eventually (in late-phase of the disease), the altered phosphorylation state of eIF2alpha evoked by Abeta may account for the decreased efficacy of mRNA translation and de novo protein synthesis required for synaptic plasticity, and may consequently be one of molecular causes for impairment of cognitive functions exhibited in the early phase of AD patients.
ISSN
0360-4012 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17393484

http://hdl.handle.net/10371/23498
DOI
https://doi.org/10.1002/jnr.21267
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College of Medicine/School of Medicine (의과대학/대학원)Pharmacology (약리학전공)Journal Papers (저널논문_약리학전공)
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