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P4‐213: Novel gamma‐secretase modulators (γSecAs) increase Aβ generation by enhancing its enzymatic activity
Author(s) -
Han Jonghee,
Jang Jiyeon,
Jung Yong-Keun
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.2281
Subject(s) - amyloid precursor protein secretase , chemistry , amyloid precursor protein , ectopic expression , enzyme , in vivo , reporter gene , microbiology and biotechnology , luciferase , transfection , biochemistry , alzheimer's disease , biology , gene expression , gene , medicine , disease
Background: Amyloid plaque is a major pathological feature of Alzheimer’s disease. This glutinous body is mainly composed of amyloid-beta(A ) peptide which is cleaved from APP by two secretases, and -secretase. A has been considered as a underlying cause of the Alzheimer’s disease and is toxic in vitro and in vivo. In fact, enzymatic reaction which -secretase works is the limiting step of A generation. Thus, identification of genes that regulate it’s enzymatic activity is important for the treatment of Alzheimer’s disease. Methods: We isolated novel -secretase activator ( SecA) by using cell-based functional screening system that measures the -secretase activity-dependent fluorescence. Then, AICDluciferase reporter assay reflecting -secretase activity confirmed the stimulatory effects of the clones. Results: Ectopic expression of SecA1 and SecA3 increased -secretase-mediated cleavage of CTF in SY5Y-CTF cells. In ELISA assay, ectopic expression of SecA1 and SecA3 increased the amount of A peptides, which was significantly suppressed by the -secretase inhibitor, L645.458. Enzymatic activities of -secretase, but not -secretase, were significantly enhanced by SecA1 and SecA3 in SY5Y-APPsw cells. Conversely, the enhanced -secretase activity was suppressed by shRNA SecA. More importantly, SecA seems to not affect notch cleavage in the NICD-luciferase reporter assay. Conclusions: These results suggest that SecA may regulate -secretase activity and thus increase A generation.