Swedish amyloid precursor protein mutation increases phosphorylation of eIF2alpha in vitro and in vivo.
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.
Kim
Hye-Sun
HS
Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul, South Korea.
Choi
Yoori
Y
Shin
Ki-Young
KY
Joo
Yuyoung
Y
Lee
Yong-Kyu
YK
Jung
Sang Yong
SY
Suh
Yoo-Hun
YH
Kim
Joung-Hun
JH
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016022:Case-Control Studies; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D016555:Matched-Pair Analysis; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014162:Transfection; D014810:Vitamin E / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D015852:Eukaryotic Initiation Factor-2; D017382:Reactive Oxygen Species; D014810:Vitamin E