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11
long-term potentiation (LTP, a cellular model believed to underlie learning and memory) and scavengers of superoxide blocked LTP (Klann E, 1998). Hippocampus-dependent memory is impaired in young Cu/Zn-SOD or EC-SOD overexpressed mice (Serrano F et al., 2004). But aged EC-SOD transgenic mice exhibited better hippocampus-dependent spatial learning (Hu D et al., 2006).
Activation of p44/42 MAPK (i.e. ERK1/2) signaling pathway is involved in learning and memory. ERK was found to be rapidly activated after LTP and this activation was required for the induction of LTP in rat hippocampus (English JD et al., 1997). Systemic administration of an inhibitor of MEK1 (activator of MAPK) caused impairment in contextual and auditory fear conditioning (Atkins CM et al., 1998). Mice expressing dominant-negative MEK1 in the forebrain showed decreased ERK activation in the hippocampus and impaired spatial memory and impaired contextual fear conditioning while auditory fear conditioning remained intact (Kelleher RJ et al., 2004).
Oxidative stress is involved in several neurodegenerative diseases. Oxidative stress is thought to play a significant role in both the onset and progression of Alzheimer's disease. Oxidation of lipids, protein and nucleic acids are found in AD patients and in animal models (Smith MA et al., 2000). Actually, oxidatively modified macromolecules precede A beta plaque deposition in transgenic mouse models of AD. Decreased expression of MnSOD, a major antioxidant enzyme, in APP mutant mice led to increased Abeta plaque (Li F et al., 2004). On the other hand, antioxidant vitamin E reduced Abeta deposition in
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 21 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 11 long-term potentiation (LTP, a cellular model believed to underlie learning and memory) and scavengers of superoxide blocked LTP (Klann E, 1998). Hippocampus-dependent memory is impaired in young Cu/Zn-SOD or EC-SOD overexpressed mice (Serrano F et al., 2004). But aged EC-SOD transgenic mice exhibited better hippocampus-dependent spatial learning (Hu D et al., 2006). Activation of p44/42 MAPK (i.e. ERK1/2) signaling pathway is involved in learning and memory. ERK was found to be rapidly activated after LTP and this activation was required for the induction of LTP in rat hippocampus (English JD et al., 1997). Systemic administration of an inhibitor of MEK1 (activator of MAPK) caused impairment in contextual and auditory fear conditioning (Atkins CM et al., 1998). Mice expressing dominant-negative MEK1 in the forebrain showed decreased ERK activation in the hippocampus and impaired spatial memory and impaired contextual fear conditioning while auditory fear conditioning remained intact (Kelleher RJ et al., 2004). Oxidative stress is involved in several neurodegenerative diseases. Oxidative stress is thought to play a significant role in both the onset and progression of Alzheimer's disease. Oxidation of lipids, protein and nucleic acids are found in AD patients and in animal models (Smith MA et al., 2000). Actually, oxidatively modified macromolecules precede A beta plaque deposition in transgenic mouse models of AD. Decreased expression of MnSOD, a major antioxidant enzyme, in APP mutant mice led to increased Abeta plaque (Li F et al., 2004). On the other hand, antioxidant vitamin E reduced Abeta deposition in |
