碩士 / 國立臺灣師範大學 / 生命科學系 / 103 / Alzheimer's disease (AD) is the most common form of dementia in the elderly. AD is a progressive and irreversible neurodegenerative disorder that results in significant memory loss and behavioral and personality changes. The two hallmarks of AD, the amyloid plaques and neurofibrillary tangles (NFTs) are found in the brain of those with a diagnosis of AD. Hyperphosphorylation of tau by GSK-3β plays a crucial role in NTF formation. As GSK-3β activation is a critical step in the cascade of detrimental events in AD, therapeutics targeted to inhibiting GSK-3β may be beneficial in the treatment of this devastating disease. In the present study, computer modeling (by Dr. Ying-Chieh Sun) and experimental analysis were used to assist discovery/design of GSK-3β inhibitors. To obtain sufficient enzyme sample for the inhibitor screening, human GSK-3β gene has been cloned and expressed in several E. coli strains. However, the recombinant GSK-3β was expressed as inclusion bodies. Conditions of protein expression and protein refolding were further optimized to express active soluble protein and still cannot improve the solubility of recombinant GSK-3β. GSK-3β assay has been established by using commercial human GSK-3β to screen for potent inhibitors. Three of the 38 compounds predicted by computer modeling have been tested to be potent inhibitors with a residual activity lower than 65% of the activity without inhibitor. These three inhibitors could be applied in the treatment of AD.
| Identifer | oai:union.ndltd.org:TW/103NTNU5112018 |
| Date | January 2015 |
| Creators | Huang, Wun-Han, 黃汶函 |
| Contributors | Lee, Guan-Chiun, 李冠群 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 66 |
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