Master of Science
Meredith Protas, PhD
Pankaj Kapahi, PhD
Durai Sellegounder, PhD
Aging is the largest risk factor for the development of Alzheimer’s disease (AD) and related dementias. A recently proposed driver of age-related pathologies is cellular senescence, a phenotype that consists of cell-cycle arrest and an inflammatory response known as the senescence-associated secretory phenotype (SASP). Although there is a link between the accumulation of senescent cells and neurodegeneration, much remains unknown about how senescent cells arise in the brain. Astrocytes are the most abundant cell type in the brain that serve important roles like supporting neurons and proliferating in response to stress. Methylglyoxal (MGO) is a glycolytic byproduct that can react with biomolecules to form toxic advanced glycation end-products (AGEs) that have been implicated in age-related diseases, and which we hypothesize may trigger astrocytic senescence. In this study, we found that primary mouse astrocytes exposed to MGO exhibited a weak senescence response, while astrocytes from the human U-87 cell line showed greater signs of senescence. We show that mouse astrocytes express higher glyoxalase activity, which may explain the weaker senescence response compared to human astrocytes. The transient receptor potential ankyrin 1 (TRPA1) ion channel has been shown to sense and detoxify high levels of MGO. Here, we also found that loss of the TRPA1 channel in primary mouse astrocytes and mice led to signs of decreased senescence and other unexpected changes. Our preliminary results suggest a key role of MGO and the TRPA1 channel in mediating senescence and neurodegeneration, and more studies will need to be performed to determine the therapeutic potential of these endogenous targets.
Hill, Natalie, "Determining the role of methylglyoxal (MGO) and the TRPA1 channel in inducing astrocyte senescence and neurodegeneration" (2021). Natural Sciences and Mathematics | Biological Sciences Master's Theses. 16.
Available for download on Friday, May 31, 2024