Effect of ischemic neuronal insults on amyloid precursor protein processing.
The nature of the association between ischemic stroke and Alzheimer's disease (AD) at the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insults on the regulation of amyloid precursor protein (APP) processing. We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation) to evaluate the effect of ischemic neuronal insults on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line and primary cultured cells of transgenic mice which expressed human APP (Tg2576). Ischemic neuronal insults increased the production of Abeta in Tg2576 primary culture cells compared to controls. A disintegrin and metalloprotease 10 (ADAM 10) was markedly increased in early stage of ischemic insults, which was followed by decreased level of ADAM 10 expression in later stage. The protein and mRNA expression of beta-site cleavage enzyme (BACE) and BACE activity was not significantly different between the group of ischemic insults and control. By contrast, the activity of gamma-secretase was significantly increased after 4 h of ischemic insults, as compared to controls. The present study showed that the ischemic neuronal insults increased the production of Abeta by influencing APP metabolism, which may link the role of ischemic insults to the pathogenesis of AD.
Lee
Phil Hyu
PH
Department of Neurology, Ajou University School of Medicine, Woncheon-dong San 5, Suwon, Gyungki-do 442-749, South Korea.
Hwang
Eun Mi
EM
Hong
Hyun Seok
HS
Boo
Jung Hyun
JH
Mook-Jung
Inhee
I
Huh
Kyoon
K
D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001483:Base Sequence; D002545:Brain Ischemia / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse