Study of Inhibitory Mechanisms of Isovitexin on β-Site APP Cleaving Enzyme Expression in Human Neuroblastoma SH-SY5Y Cells
| Autor: | Chin-Hsuan Lin, 林錦萱 |
|---|---|
| Rok vydání: | 2009 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 97 Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. The processing of �namyloid precursor protein (APP) is initiated by beta-site APP cleaving enzyme 1 (BACE1) cleavage, which produce beta-cleaved C-terminal fragment (C99), and then further cleaved by γ-secretase leads to amyloid β-peptide (Aβ��)formation. Generation and deposition of Aβ is central to the aetiology of AD. Herein, BACE1 is a rate-limiting enzyme in the production of Aβ. Consequently, the enzyme activity, mRNA and protein levels of BACE1 are elevated in AD patients. So the inhibition of BACE1 is an attractive therapeutic target for the treatment of AD. Our previous BACE1 inhibitor screening model discovered that isovitexin is a potential BACE1 inhibitor. Therefore, the aim of this study is to evaluate possible pharmacologic inhibitory mechanisms of isovitexin on BACE1. The in vitro results showed that isovitexin suppressed BACE1 activity in human platelet and SH-SY5Y total protein. Isovitexin also inhibited BACE1 activity in SH-SY5Y cell model, since it indeed attenuated C99，intra- and extra- cellular Aβ���nproduction. The isovitexin did not obviously influence on cell viability. Besides, it major via inhibited BACE1 protein expression, thereby inhibited the production of C99 and Aβ. Lower expression of BACE1 protein maybe derive from isovitexin enhanced BACE1 degradation or attenuated BACE1 gene expression. This study also showed that isovitexin did not promote BACE1 degradation but influence on BACE1 mRNA stability. In summary, isovitexin probably inhibited BACE1 protein expression through interfere BACE1 mRNA stability, although other involved mechanisms were not excluded. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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