콜린성 신경세포에서 Honokiol에 의한 Tau 단백질 인산화의 억제효과
Inhibitory Effect of Honokiol on Tau Phosphorylation in Cholinergic Neurons
- 발행기관 아주대학교
- 지도교수 Young-Don Lee
- 발행년도 2011
- 학위수여년월 2011. 2
- 학위명 석사
- 학과 및 전공 일반대학원 분자과학기술학과
- 실제URI http://www.dcollection.net/handler/ajou/000000011554
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Hyperphosphorylation of tau protein and subsequent formation of neurofibrillary tangle is the main pathological feature observed in Alzheimer’s disease (AD) brain. One of the key enzymes which are responsible for hyperphosphorylation of tau is glycogen synthase kinase-3β (GSK3β). In this respect, inhibition of GSK3β activity has been considered as a therapeutic target for AD suppression or treatment. Here the inhibitory effects of honokiol, a major constituent isolated from the bark of Magnolia obovata Thunb, on tau hyperphosphorylation and cell death in cholinergic neuroblastoma cell lines were described. In LA-N2 cells, a human cell line, the effects of honokiol on tau abnormal phosphorylation under amyloid-beta (Aβ) exposure was primarily observed. In differentiated SN56.B5.G4 (SN56) cells, a mouse cell line, honokiol not only protected SN56 cells from Aβ-induced toxicity, but also ameliorated the Aβ-induced abnormal tau phosphorylation. In addition, it was observed that honokiol inhibited GSK3β activity in a dose-dependent manner, its effect as good as other well-known GSK3β inhibitors, alsterpaullone and lithium chloride. It was also found that honokiol promoted Akt activity, implying that Akt was involved in the effect of honokiol on GSK3β activity. Honokiol also inhibited cycline dependent protein kinase 5 (Cdk5) activity, which is another major kinase for hyperphosphorylation of tau. Taken together, these results suggest that honokiol may be a new potential natural compound that is relevant for the treatment of AD.
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ABSTRACT I
CONTENTS II
LIST OF FIGURES IV
LIST OF TABLES V
LIST OF ABBREVIATIONS VI
I. INTRODUCTION
1. Alzheimer’s disease 1
2. Tau protein 2
3. Cholinergic neurons 4
4. Honokiol 4
5. Purpose 5
II. MATERIALS AND METHODS
A. MATERIALS 6
B. METHODS
1. Cell culture and differentiation 8
2. Preparation of oligomeric Aβ25-35 and treatment of examined compounds
8
3. MTT assay 10
4. Immunoblotting analysis 10
5. Immunocytochemistry 10
6. GSK3β and Cdk5 kinase assay 11
III. RESULTS
1. Honokiol reduced Aβ25-35-induced cytotoxicity on LA-N2 cells 12
2. CNTF triggered differentiation on SN56.B5.G4 cells 14
3. Aβ25-35 induced abnormal tau phosphorylation in SN56 cells 16
4. Honokiol protected SN56 cells from Aβ25-35-induced neurotoxicity 18
5. Honokiol decreased phosphorylation of tau in SN56 cells under
Aβ25-35 exposure 20
6. Honokiol inhibited elevated GSK3β activity by Aβ25-35 23
7. Honokiol promoted Akt activity 25
8. Honokiol decreased Cdk5 activity 26
9. Tau-tg mice P301L showed high expression of phospho-tau and total tau
27
IV. DISCUSSION 29
V. CONCLUSION 33
VI. REFERENCE 34
국문초록 41
