아밀로이드베타로 유도된 신경세포사멸에서 PP2A 활성 조절을 통한 도네페질의 신경보호 작용
- Title
- 아밀로이드베타로 유도된 신경세포사멸에서 PP2A 활성 조절을 통한 도네페질의 신경보호 작용
- Other Titles
- Neuroprotective effects of donepezil through regulation of PP2A activity in amyloid-beta-induced neuronal death
- Author
- 노민영
- Alternative Author(s)
- Noh, Min Young
- Advisor(s)
- 김승현
- Issue Date
- 2011-02
- Publisher
- 한양대학교
- Degree
- Doctor
- Abstract
- Hyperphosphorylated isoforms of the microtubule-associated protein tau are the major components of the neurofibrillary tangles observed in the brains of Alzheimer's disease (AD) patients. Glycogen synthase kinase-3? (GSK-3?) and protein phosphatase-2A (PP2A) play essential roles in the regulation of tau phosphorylation and have been suggested to be involved in abnormal tau phosphorylation and aggregation in AD. Donepezil is a reversible, noncompetitive acetylcholinesterase (AChE) inhibitor used as a treatment for AD. Donepezil was recently shown to have neuroprotective effects mediated through GSK-3? inhibition. However, effects of donepezil on protein phosphatase 2A (PP2A) have not yet been clearly established. We investigated whether PP2A is involved in the protective effects of donepezil against amyloid-beta (1-42) (A?42)-induced neurotoxicity. Primary cultured cortical neurons were pre-treated with several concentrations of donepezil for 24 h followed by treatment with 20 ?M A?42 for 6 h. Donepezil protected neurons from A?42-induced toxicity. PP2A activity was increased in neurons pre-treated with donepezil when compared to cells without treatment. The PP2A-activating effect of donepezil was achieved by increasing methylated PP2A and reducing demethylated PP2A, as confirmed by western blotting. Donepezil-induced PP2A activation was reversed by treatment with the PP2A inhibitor okadaic acid (OA) (50 nM). Moreover, inhibition of PP2A enhanced the phosphorylation of tau, a process that was inhibited by donepezil. These results suggest that donepezil activates PP2A, thereby regulating tau phosphorylation. These findings also suggest that the donepezil-induced activation of PP2A partly mediates donepezil?s neuroprotective effect.
- URI
- https://repository.hanyang.ac.kr/handle/20.500.11754/140249http://hanyang.dcollection.net/common/orgView/200000416502
- Appears in Collections:
- GRADUATE SCHOOL[S](대학원) > MEDICINE(의학과) > Theses (Ph.D.)
- Files in This Item:
There are no files associated with this item.
- Export
- RIS (EndNote)
- XLS (Excel)
- XML