Honors College Thesis
 

The Role of Nrf2 in Brain Cellular Senescence

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https://ir.library.oregonstate.edu/concern/honors_college_theses/qv33s375t

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  • Aging is a major risk factor for the deterioration of biochemical pathways that lead to many chronic neurodegenerative disorders (i.e. Parkinson’s and Alzheimer's Disease). Cellular senescence is a hallmark of aging, a condition characterized by stable growth arrest resulting in a cell that no longer divides, but is metabolically active. A senescent cell leaks a mixture of proinflammatory cytokines and other factors, collectively called the senescence-associated secretory phenotype (SASP), that become toxic to neighboring cells. Removal of senescent cells has previously been shown to promote healthy tissue function and delay age-associated pathologies in mice. Nrf2 is a transcriptional factor involved in regulating the cell’s response to stress. Mice without the gene for Nrf2 (Nrf2KO) show increased age-related diseases, including cognitive decline. Previous studies in our lab have shown that Nrf2KO mice have higher levels of cellular senescence in many tissues. This study addressed the hypothesis that an absence of Nrf2 will lead to an increase in cellular senescence in the hippocampus, and be a driver for age-associated cognitive decline and neurodegeneration in mice. Via SA-β-galactosidase staining, qPCR, Western Blotting and Immunohistochemistry, the levels of senescent cell markers (p16, p21, SA-β-gal, and SASP members) were experimentally determined to be higher in the hippocampus of Nrf2KO mice compared to WT. Treatment with Rapamycin (a mTOR inhibitor that inhibits cellular senescence) and Senolytics (drugs that selectively kill senescent cells) had a mild effect on levels of senescence in the Nrf2KO and WT mice. Behavioral tests demonstrated Nrf2KO mice had less cognitive flexibility, and that Rapamycin significantly increased the performance of both Nrf2 KO and WT groups. Our data suggests Nrf2 is a powerful influencer of cellular senescence in the hippocampus of mice, and Rapamycin and Senolytics may be promising therapies for cognitive decline by targeting cellular senescence.
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  • Pending Publication
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  • 2020-02-28 to 2021-03-29

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