Cellular senescence, a hallmark of aging, has been implicated in the pathogenesis of many major age-related disorders, including atherosclerosis, metabolic disease, and neurodegenerative disorders such as Alzheimer's disease (AD). AD is characterized by increased cognitive impairment and treatment options available provide minimal disease attenuation. Additionally, diagnostic methods for AD are not conclusive with definitive diagnoses requiring postmortem brain evaluations. Therefore, miRNAs, a class of small, non-coding RNAs, have garnered attention for their ability to regulate a variety of mRNAs and their potential to serve as both therapeutic targets and biomarkers of disease. Several miRNAs have already been implicated with AD and cellular senescence and have been found to directly target genes associated with their pathology. The APP/PS1 mice is an AD model that expresses the human mutated form of the amyloid precursor protein (APP) and presenilin-1 (PS1) genes. In a previous study, crossing long-living growth hormone (GH)-deficient Ames dwarf (df/df) mice with APP/PS1 mice provided protection from AD through a reduction in IGF-1, amyloid-ß (Aß) deposition, and gliosis. Hence, we hypothesized that changes in the expression of miRNAs associated with AD mediated such benefits. To test this hypothesis, we sequenced miRNAs in hippocampi of df/df, wild type (+/+), df/+/APP/PS1 (phenotypically normal APP/PS1), and df/df/APP/PS1 mice. Results of this study demonstrated significantly upregulated and downregulated miRNAs between df/df/APP/PS1 and df/+/APP/PS1 mice that suggest the df/df mutation provides protection from AD progression. Furthermore, we identified a pro-longevity miRNA, miR-449a-5p, downregulated with age in normal mice but maintained in long-living df/df mice. Gene target analysis and our functional study with miR-449a has revealed its potential as an anti-senescence therapeutic. We tested the hypothesis that miR-449a reduces cellular senescence by targeting senescence-associated genes induced in response to strong mitogenic signals and other damaging stimuli and found miR-449a upregulation reduces senescence, primarily through targeted reduction of p16Ink4a, p21Cip1, and the PI3K-mTOR signaling pathway. Our results demonstrate that miR-449a is important in modulating key signaling pathways that control cellular senescence and age-related pathologies and that miRNAs hold great potential as therapeutics and/or biomarkers for disease, namely in Alzheimer's disease.
| Identifer | oai:union.ndltd.org:ucf.edu/oai:stars.library.ucf.edu:etd2020-2418 |
| Date | 01 January 2022 |
| Creators | Noureddine, Sarah |
| Publisher | STARS |
| Source Sets | University of Central Florida |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses and Dissertations, 2020- |
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