Effect of Ischemic Neuronal Insults on Amyloid Precursor Protein Processing

J Korean Neurol Assoc > Volume 23(2); 2005 > Article

Journal of the Korean Neurological Association 2005;23(2): 241-248.

허혈성 신경세포손상이 아밀로이드 전구단백질의 대사에 미치는 영향

이필휴, 황은미* 묵인희* 허 균 최일생

아주대학교 의과대학 신경과학교실, 서울대학교 의과대학 생화학교실*, 연세대학교 의과대학 신경과학교실

Effect of Ischemic Neuronal Insults on Amyloid Precursor Protein Processing

Phil Hyu Lee

Department of Neurology, Ajou University School of Medicine, Suwon; Department of Biochemistry, Seoul National University School of Medicine*, Seoul, Department of Neurology, Yonsei University College of Medicine†, Seoul, Korea

Abstract

Background: In spite of the different pathogenesis and exclusive respect in the diagnosis of Alzheimer's disease (AD) and vascular dementia (VaD), recent epidemiological and pathological studies indicates that ischemic stroke have an important role in the pathogenesis of both VaD and AD. However,the association of ischemic stroke and AD on the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insult on the regulation of amyloid precursor protein (APP) processing.
Methods: We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation, OGD) to evaluate the effect of ischemic insult on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line, SH-SY5Y, and primary cultured cells of Tg2576 APP transgenic mouse.
Results: Ischemic insult significantly increased the beta amyloid (Aβ) production in the primary cultured cells of Tg2576 APP transgenic mice (p<0.001). A disintegrin and metalloprotease 10 (ADAM 10), a candidate of α- secretase, was markedly increased in the early stage of ischemic insult (up to 2 hours of OGD, p<0.001; 4 hours of OGD, p<0.05), which was followed by the decreased level of ADAM 10 expression in a later stage (p<0.001). However, the protein and mRNA expression of β-site cleavage enzyme (BACE) and BACE activity were not significantly different between the group of ischemic insult and control. By contrast, the activity of γ-secretase was significantly increased after 4 hours of ischemic insult, as compared to controls.
Conclusions: This study demonstrates that the ischemic neuronal insults increase the production of Aβ via activation of the amyloidogenic pathway, which may link the role of ischemic insults to the pathogenesis of AD.KeyWords:Ischemic neuronal insult, Amyloid precursor protein, Beta-amyloid, α-,β-,γ-secretase