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ESTROGEN REGULATION OF BIOENERGETICS AND
MITOCHONDRIAL FUNCTION:
IMPLICATIONS FOR ALZHEIMER’S DISEASE RISK AND THERAPEUTICS
by
Jia Yao
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
May 2010
Copyright 2010 Jia Yao
Object Description
| Title | Estrogen regulation of bioenergetics and mitochondrial function: implications for Alzheimer's disease risk and therapeutics |
| Author | Yao, Jia |
| Author email | jiayao@usc.edu; uscjiayao@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology & Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2010-03-24 |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-05-04 |
| Advisor (committee chair) | Brinton, Roberta |
| Advisor (committee member) |
Cadenas, Enrique Alkana, Ronald Baudry, Michel |
| Abstract | Presented here are a collection of studies that build on our existing knowledge of estrogen actions on brain mitochondria. Previous studies from our lab as well as other colleagues have demonstrated that estrogen (E2, 17β-estradiol) is neuroprotective against neurotoxic insults including exposure to glutamate and amyloid beta (Aβ) (Nilsen et al, 2006; Simpkins and Dykens, 2007; Vina et al, 2007b). Further, the E2 induced neuroprotective mechanisms converge on mitochondria (Brinton, 2008b; Nilsen and Diaz Brinton, 2003; Nilsen et al, 2007). In the current research project, we have hypothesized that mitochondria, particularly mitochondrial bioenergetics play a pivotal role in the pathogenesis of age-related Alzheimer’s disease (AD) whereas estrogen proactively sustains and enhances mitochondrial function that was compromised in aging and AD. To test our hypotheses, we have conducted a combination of in vitro and in vivo analyses which address four specific aims. Specific Aim 1 (Chapter 2) serves to investigate the role of mitochondrial bioenergetic deficits in AD pathogenesis using the triple transgenic Alzheimer’s mouse model. Specific Aim 2 (Chapter 3) serves to determine the impact of E2 deficiency on mitochondrial function and AD progression. Specific Aim 3 (Chapter 4) seeks to investigate the underlying mechanism of estrogen induced neuroprotection as well as to examine the role of different estrogen receptors in estrogen action in the brain. Specific Aim 4 (Chapter 5) focuses on the therapeutic implications of the findings from the previous three aims and introduces a novel therapeutic strategy targeting mitochondria for preventing AD and/or delaying the progression of AD.; Data from these four specific aims have demonstrated that: 1) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in the 3xTgAD mouse model. 2) Loss of ovarian hormones either due to age-related reproductive senescence or surgical ovariectomy (OVX) significantly exacerbates mitochondrial dysfunction that occurs in aging or AD. 3) E2 treatment initiated at the time of OVX prevented the OVX-induced mitochondrial deficits by sustaining mitochondrial bioenergetic capacity, decreasing oxidative stress, and preventing mitochondrial amyloid and ABAD induction. 4) Therapeutic strategies targeting mitochondria could alter AD progression by manipulating brain mitochondrial bioenergetic profile.; We believe that findings from these studies will expand our understanding of the mechanism of AD pathogenesis as well as the pharmacological pathway of estrogen induced neuroprotection against AD. Our research will also enable the development of novel therapeutics that target mitochondrial bioenergetics for the prevention and treatment of AD and other neurodegenerative diseases that could be partially attributed to mitochondrial dysfunction. |
| Keyword | Alzheimer's disease; estrogen; mitochondria; bioenergetics; therapeutics |
| 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-m2999 |
| Rights | Yao, Jia |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Yao-3656 |
| Archival file | uscthesesreloadpub_Volume44/etd-Yao-3656.pdf |
Description
| Title | Page 1 |
| Full text | ESTROGEN REGULATION OF BIOENERGETICS AND MITOCHONDRIAL FUNCTION: IMPLICATIONS FOR ALZHEIMER’S DISEASE RISK AND THERAPEUTICS by Jia Yao A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR PHARMACOLOGY AND TOXICOLOGY) May 2010 Copyright 2010 Jia Yao |
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