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iv
Table of Contents
Acknowledgements ................................................................................................................... ii
List of Figures ........................................................................................................................... vi
Abstract .................................................................................................................................... ix
Chapter 1. Background and significance ................................................................................... 1
1.1. Oxidative Stress and Aging .............................................................................................. 1
1.1.1. Oxidative stress and aging .......................................................................................... 1
1.1.2. Pro-aging roles of insulin/IGF-I system ...................................................................... 3
1.1.3. Calorie restriction and aging ....................................................................................... 4
1.2. Sir2 in Oxidative Stress and Aging ................................................................................... 6
1.3. Long Term Potentiation in Learning and Memory ........................................................... 8
1.4. Oxidative Stress and ERK1/2 signaling in Normal Brain Function and Brain Disease .................................................................................................................................... 10
Chapter 2. Role of SIRT1 in IGF-I/ERK signaling and neuronal oxidative stress .................. 13
2.1. Summary ......................................................................................................................... 13
2.2. Introduction ..................................................................................................................... 13
2.3. Methods and Materials .................................................................................................... 17
2.4. Results ............................................................................................................................. 23
2.4.1. Inhibition of SIRT1 increases oxidative stress resistance in neurons ....................... 23
2.4.2. SIRT1 inhibition does not alter antioxidant enzyme expression in cultured neurons .................................................................................................................................... 30
2.4.3. SIRT1 does not alter the activation of Akt or CREB in cultured neurons ................ 31
2.4.4. SIRT1 inhibition decreases Ras/ERK activation in culture and in vivo ................... 34
2.4.5. Subcellular localization of SIRT1 in the brain .......................................................... 39
2.4.6. SIRT1 regulates Ras/ERK activity through deacetylating IRS-2 ............................. 43
2.4.7. MEK/ERK1/2 inhibition protects neurons against oxidative stress .......................... 46
2.4.8. Reduced oxidative brain damage and life span of SIRT1 knockout mice ................ 50
2.5. Discussion ....................................................................................................................... 54
Chapter 3. Role of SIRT1 in synaptic plasticity, learning and memory .................................. 62
3.1. Summary ......................................................................................................................... 62
3.2. Introduction ..................................................................................................................... 63
3.3. Methods and Materials .................................................................................................... 66
3.4. Results ............................................................................................................................. 76
3.4.1. SIRT1 deficiency does not alter gross brain anatomy .............................................. 76
3.4.2. SIRT1 is essential for normal cognitive capabilities in mice .................................... 79
3.4.3. Effect of SIRT1 overexpression on learning and memory ........................................ 89
3.4.4. Impaired LTP in SIRT1 knockout hippocampus ...................................................... 98
3.4.5. Overexpression of SIRT1 in brain has no effect on long-term potentiation ........... 102
3.5. Discussion ..................................................................................................................... 106
Object Description
| Title | Roles of SIRT1 in neuronal oxidative damage and brain function |
| Author | Li, Ying |
| Author email | lying@usc.edu; yingraceli@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2008-09-12 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-10-30 |
| Advisor (committee chair) | Longo, Valter D. |
| Advisor (committee member) |
Baudry, Michel Pike, Christian J. Madigan, Stephen A. |
| Abstract | Aging is a common phenomenon of multiple organisms. In humans aging is frequently accompanied by cognitive decline and occurrence of neurodegenerative diseases which reduce the quality of life and impose financial stress on society. Delaying the aging process, extending life span and decreasing the occurrence of age-related brain function deficit have always been aspirations of human kind. Extensive research has advanced our understanding of the mechanisms underlying aging, among which is the ability of calorie restriction to increase longevity, and the pivotal regulatory roles of insulin/IGF-1 signaling pathway. Some recent studies identified silent information regulator 2 (Sir2; SIRT1 is the mammalian homolog) as a key mediator of the beneficial effects of calorie restriction and this prompted development of SIRT1 activators for human consumption to delay aging and accompanying cognitive decline. However, our laboratory previously showed in yeast that Sir2 can increase stress sensitivity and limit life span extension under certain conditions, calling for more detailed characterization of SIRT1. In the research described in this dissertation I extended this study to the mammalian system and focused on the role of SIRT1 on the health of neurons and brain functions, especially learning and memory.; This dissertation consists of three chapters. In chapter 1 I briefly review some recent progress on aging, oxidative stress, insulin/IGF-1 signaling pathway and learning and memory with emphasis on the involvement of SIRT1 in these processes. In chapter 2 I focused on the role of SIRT1 in oxidative stress in neurons and its mechanisms. I found that SIRT1 inhibition increased resistance to oxidative damage and this effect is partially mediated by a reduction in IGF-I/IRS-2/Ras/ERK1/2 signaling. In chapter 3 I studied the functions of SIRT1 in learning and memory. The experiments showed that deletion of SIRT1 impairs a certain form of synaptic plasticity and reduce performance in several different learning and memory tasks while overexpressing SIRT1 did not substantially affect learning and memory.; Together, my studies reveal that SIRT1 exacerbates neuronal oxidative damage but is essential in learning and memory, indicating that SIRT1 plays multiple roles in aging and brain functions and that caution should be exercised in designing anti-aging or therapeutic approaches that involve targeting SIRT1. |
| Keyword | SIRT1; neurons; brain; oxidative damage; learning and memory |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m1723 |
| Contributing entity | University of Southern California |
| Rights | Li, Ying |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-LI-2405 |
| Archival file | uscthesesreloadpub_Volume44/etd-LI-2405.pdf |
Description
| Title | Page 4 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | iv Table of Contents Acknowledgements ................................................................................................................... ii List of Figures ........................................................................................................................... vi Abstract .................................................................................................................................... ix Chapter 1. Background and significance ................................................................................... 1 1.1. Oxidative Stress and Aging .............................................................................................. 1 1.1.1. Oxidative stress and aging .......................................................................................... 1 1.1.2. Pro-aging roles of insulin/IGF-I system ...................................................................... 3 1.1.3. Calorie restriction and aging ....................................................................................... 4 1.2. Sir2 in Oxidative Stress and Aging ................................................................................... 6 1.3. Long Term Potentiation in Learning and Memory ........................................................... 8 1.4. Oxidative Stress and ERK1/2 signaling in Normal Brain Function and Brain Disease .................................................................................................................................... 10 Chapter 2. Role of SIRT1 in IGF-I/ERK signaling and neuronal oxidative stress .................. 13 2.1. Summary ......................................................................................................................... 13 2.2. Introduction ..................................................................................................................... 13 2.3. Methods and Materials .................................................................................................... 17 2.4. Results ............................................................................................................................. 23 2.4.1. Inhibition of SIRT1 increases oxidative stress resistance in neurons ....................... 23 2.4.2. SIRT1 inhibition does not alter antioxidant enzyme expression in cultured neurons .................................................................................................................................... 30 2.4.3. SIRT1 does not alter the activation of Akt or CREB in cultured neurons ................ 31 2.4.4. SIRT1 inhibition decreases Ras/ERK activation in culture and in vivo ................... 34 2.4.5. Subcellular localization of SIRT1 in the brain .......................................................... 39 2.4.6. SIRT1 regulates Ras/ERK activity through deacetylating IRS-2 ............................. 43 2.4.7. MEK/ERK1/2 inhibition protects neurons against oxidative stress .......................... 46 2.4.8. Reduced oxidative brain damage and life span of SIRT1 knockout mice ................ 50 2.5. Discussion ....................................................................................................................... 54 Chapter 3. Role of SIRT1 in synaptic plasticity, learning and memory .................................. 62 3.1. Summary ......................................................................................................................... 62 3.2. Introduction ..................................................................................................................... 63 3.3. Methods and Materials .................................................................................................... 66 3.4. Results ............................................................................................................................. 76 3.4.1. SIRT1 deficiency does not alter gross brain anatomy .............................................. 76 3.4.2. SIRT1 is essential for normal cognitive capabilities in mice .................................... 79 3.4.3. Effect of SIRT1 overexpression on learning and memory ........................................ 89 3.4.4. Impaired LTP in SIRT1 knockout hippocampus ...................................................... 98 3.4.5. Overexpression of SIRT1 in brain has no effect on long-term potentiation ........... 102 3.5. Discussion ..................................................................................................................... 106 |
