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아밀로이드 베타에 의한 mTORC1 활성이 cyclin/CDK 매개 신경세포 자멸사에 미치는 영향 : Amyloidβ-Induced mTORC1 Activation Up-Regulates cyclinD1/CDK4 and cyclinE/CDK2 Levels Leading to Neuronal Apoptosis
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 한호재 | - |
dc.contributor.author | 이기훈 | - |
dc.date.accessioned | 2017-07-19T11:33:33Z | - |
dc.date.available | 2017-07-19T11:33:33Z | - |
dc.date.issued | 2016-08 | - |
dc.identifier.other | 000000136557 | - |
dc.identifier.uri | https://hdl.handle.net/10371/133762 | - |
dc.description | 학위논문 (석사)-- 서울대학교 대학원 : 수의학과, 2016. 8. 한호재. | - |
dc.description.abstract | Alzheimer's disease (AD) is a neurodegenerative disorder induced by Amyloid β (Aβ) resulting in tau hyper-phosphorylation which is associated with neuronal apoptosis. Because no therapeutic targets for AD have been identified yet, I investigated relationship of cyclin-dependent kinases (CDKs) with tau phosphorylation in Aβ-induced neuronal apoptosis. In the present study, Aβ induced apoptosis in a time-dependent manner. Aβ increased the calcium influx which was dependent on the L-type calcium channel. I showed that the Aβ increased ROS (Reactive oxygen species) generation was blocked by EGTA (extracellular calcium chelator) but not by BAPTA-AM (intracellular calcium chelator) indicating that Aβ-induced calcium influx up-regulates ROS. The Aβ-induced ROS increased the HIF-1α expression which was blocked by N-acetyl-L-cysteine (NAC, ROS scavenger). Through HIF-1α siRNA transfection, I determined that Aβ stimulates mTORC1 phosphorylation through PI3K/AKT signaling. Moreover, my results show that Aβ-induced mTOR activation inhibits autophagy, while Aβ-activated mTOR increases cyclinD1/CDK4 and cyclinE/CDK2 expression. Interestingly, Aβ-inhibited autophagy up-regulated cyclinD1/CDK4 and cyclinE/CDK2 which were blocked by Trehalose (an autophagy inducer). These results suggest that Aβ-induced mTOR activation up-regulates the expression of cyclins and CDKs while the accumulation of cyclins and CDKs is attributed to Aβ-inhibited autophagy. CDKs were directly bound to tau, and leaded to phosphorylating tau which was blocked by Flavopiridol (CDK inhibitor). Phosphorylation of tau induced detachment from microtubule leading microtubule destabilization-mediated neuronal apoptosis which was blocked by Paclitaxel (microtubule stabilizer). In conclusion, Aβ-induced mTOR activation through HIF1α up-regulated the cyclinD1/CDK4 and cyclinE/CDK2 levels which were essential for tau hyper-phosphorylation leading to neuronal apoptosis. | - |
dc.description.tableofcontents | INTRODUCTION 1
MATERIALS AND METHODS 5 RESULTS 17 DISCUSSION 41 CONCLUSION 48 REFERENCES 51 ABSTRACT IN KOREAN (국문 초록) 62 | - |
dc.format | application/pdf | - |
dc.format.extent | 1794061 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Amyloid β (Aβ) | - |
dc.subject | ROS | - |
dc.subject | HIF1α | - |
dc.subject | mTOR | - |
dc.subject | CyclinD1 | - |
dc.subject | Cyclin E | - |
dc.subject | CDK4 | - |
dc.subject | CDK2 | - |
dc.subject | Autophagy | - |
dc.subject | Tau | - |
dc.subject.ddc | 636 | - |
dc.title | 아밀로이드 베타에 의한 mTORC1 활성이 cyclin/CDK 매개 신경세포 자멸사에 미치는 영향 | - |
dc.title.alternative | Amyloidβ-Induced mTORC1 Activation Up-Regulates cyclinD1/CDK4 and cyclinE/CDK2 Levels Leading to Neuronal Apoptosis | - |
dc.type | Thesis | - |
dc.description.degree | Master | - |
dc.citation.pages | 65 | - |
dc.contributor.affiliation | 수의과대학 수의학과 | - |
dc.date.awarded | 2016-08 | - |
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