Swedish amyloid precursor protein mutation increases cell cycle-related proteins in vitro and in vivo.
Reactivation of the cell cycle, including DNA replication, might play a major role in Alzheimer's disease. In this study, we report that the expressions of Swedish double mutation of amyloid precursor protein (Swe-APP) or of the APP intracellular domain (AICD) into nerve growth factor (NGF)-differentiated PC12 cells or rat primary cortical neurons increased mRNA and protein levels of cyclin D1 and cyclin B1. Treatment with lithium chloride (a glycogen synthase kinase-3beta inhibitor) down-regulated cyclin B1 induced by Swe-APP expression but up-regulated cyclin D1 expression induced by Swe-APP, suggesting that glycogen synthase kinase-3beta activity is involved in these expression changes of cyclins D1 and B1. Swe-APP, which is a prevailing cause of familial Alzheimer's disease, is well known to increase amyloid beta peptide production both in vitro and in vivo, but the underlying molecular means whereby it leads to the pathogenesis of AD remains unknown. The finding that cyclin D1 and B1 expressions were up-regulated by Swe-APP in in vitro cultured cells was substantiated in the brain tissues of Tg2576 mice, which harbor the Swe-APP mutation. These results suggest that some disturbances in cell cycle regulation may be involved in Swe-APP or AICD-induced neurodegeneration and that these contribute to the pathogenesis of AD.
Ahn
Kwang-Woo
KW
Department of Pharmacology, College of Medicine, Seoul National University, Seoul, Korea.
Joo
Yuyoung
Y
Choi
Yoori
Y
Kim
Minji
M
Lee
Sang Hyoung
SH
Cha
Seok-Ho
SH
Suh
Yoo-Hun
YH
Kim
Hye-Sun
HS
D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002453:Cell Cycle / Q000502:physiology; D019926:Cyclin B / Q000096:biosynthesis* / Q000187:drug effects; D056744:Cyclin B1; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; C534701:Ccnb1 protein, rat; D019926:Cyclin B; D056744:Cyclin B1; D004791:Enzyme Inhibitors; D019938:Cyclin D1