differential regulation of amyloid precursor proteinpresenilin 1 interaction during ab4042 production detected using fusion constructs微分调节淀粉样前体proteinpresenilin 1交互ab4042生产中检测到使用融合结构.pdfVIP

Differential Regulation of Amyloid Precursor Protein/ Presenilin 1 Interaction during Ab40/42 Production Detected Using Fusion Constructs 1,2 3 1,2 4 1,2 Naoyuki Sato *, Masayasu Okochi , Mitsuru Shinohara , Gopal Thinakaran , Shuko Takeda , 3 1 1 1 3 Akio Fukumori , Motoko Shinohara-Noma , Mari Mori-Ueda , Hizuki Hamada , Masatoshi Takeda , Hiromi Rakugi2, Ryuichi Morishita1 1 Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Yamada-oka, Suita, Japan, 2 Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Yamada-oka, Suita, Japan, 3 Department of Psychiatry and Behavioral Proteomics, Graduate School of Medicine, Osaka University, Yamada- oka, Suita, Japan, 4 Department of Neurobiology, University of Chicago, Chicago, Illinois, United States of America Abstract Beta amyloid peptides (Ab) play a key role in the pathogenesis of Alzheimer disease (AD). Presenilins (PS) function as the catalytic subunits of c-secretase, the enzyme that releases Ab from ectodomain cleaved amyloid precursor protein (APP) by intramembrane proteolysis. Familial Alzheimer disease (FAD)-linked PSEN mutations alter APP processing in a manner that increases the relative abundance of longer Ab42 peptides to that of Ab40 peptides. The mechanisms by which Ab40 and Ab42 peptides are produced in a ratio of ten to one by wild type presenilin (PS) and by which Ab42 is overproduced by FAD-linked PS variants are not completely understood. We generated chimeras of the amyloid precursor protein C-terminal fragment (C99) and PS to address thi