Browsing College of Medicine - B.Sc. (Med) Projects by Subject "Alzheimer’s Disease"
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- ItemOpen AccessExamination of Thioredoxin-1 role in pathophysiology of Alzheimer's Disease(2022-08-04) Harris, Derek; Eftekharpour, EftekharAlzheimer’s Disease (AD) is known to be associated with failure of cellular antioxidants, yet there is not much known about the impact of lowered Thioredoxin-1 level in the brain of AD patients and in AD models. Recent evidence from our lab shows that depletion of Trx1 leads to activation of Caspase-6 and induction of nuclear lamina damage, a newly proposed mechanism in pathophysiology of AD. Interestingly, the presence of nuclear lamina damage has been associated with chromatin reorganization and aberrations in epigenetic regulation, resulting in activation of repressed endogenous retroviruses that can provoke inflammation and neuronal cell death. However, it is not clear whether the axis of Trx1, Caspase-6, and nuclear lamina damage is a neuronal specific event. In this study, mouse embryonic fibroblasts (MEFs) with an inducible Cre-recombinase knockout of Trx1were used to analyze the downstream effects of Trx downregulation on this model. My results show that Trx depletion increases the prevalence of nuclear lamina damage, changes distribution of filamentous actin, alters epigenetic regulatory systems, and alters the expression of endogenous retroviruses. Additionally, it is shown that replacement of Trx1 antioxidative capacity with CB3, a cell-penetrable Trx1-mimetic peptide, ameliorates changes in actin distribution. This study provides evidence that TrxKO disrupts homeostasis in MEFs, but those changes are different from the reported results in neural cells. The results of this study have applicability for the cell-type specific characterization of Trx1 function in AD, and may have application for the design of future therapeutics.