02. Master's Thesis

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Browsing 02. Master's Thesis by Subject "Alzheimer’s Disease"

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    Assessing the role of EBV in modulation of gene expression profile of H4 neuroglioma and U118 glioblastoma cell lines consistent with Alzheimer's disease
    (Nazarbayev University School of Medicine, 2024-04-26) Omarova, Zhannur
    Epstein-Barr virus (EBV), a ubiquitous double-stranded DNA virus, also known as human herpesvirus 4, is implicated in a variety of neurological disorders. It is recognized as a major risk factor for multiple sclerosis. Recent studies have revealed a potential role for EBV infection in the pathogenesis of Alzheimer's disease (AD). EBV is known to influence host gene expression through its proteins and non-coding RNAs, including latent genes such as EBNA1 and LMP, as well as lytic genes such as BZLF1. Extensive research has examined the influence of EBV on cellular gene expression during tumorigenesis, however, little research has been conducted to understand how EBV influences gene expression associated with AD. This study aimed to explore the association between EBV and AD by testing the hypothesis that EBV elements, such as EBNA-1, cause changes in host gene expression consistent with the AD gene expression profile in the nervous tissue. To test this hypothesis, bioinformatics analysis of three GEO AD brain cell type-specific gene expression datasets was performed and the expression changes of the three identified genes – EBF1, EGR1, and GFAP – were examined in EBV-infected and uninfected H4 neuroglioma and U118 glioblastoma cell lines. EBV infection was carried out using cell-free viral supernatant. Changes in gene expression were assessed using qPCR. This study is the first to explore experimental methods for EBV infection of H4 and U118 cells. Although latent EBV infection was not detected in infected cells using primers for EBNA1, EBER1, and EBER2, the levels of EBF1, EGR1, and GFAP in infected cells changed at different days post-infection compared with control cells. Similar to AD brain cell types, EBF1 and GFAP were increased in infected U118 cells compared to uninfected cells. An increase in EGR1 was first observed in both cell lines after infection, followed by a downward trend, consistent with the results of the bioinformatics analysis. Further analysis is needed to assess whether these changes were specifically related to EBV infection. In conclusion, the thesis work highlights the need and importance of more research on the link between EBV infection and AD, as certain cellular changes after EBV infection were similar with brain cell types affected by AD.
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    ASSESSING THE ROLE OF EBV PROTEINS IN AMYLOID-BETA AGGREGATION ASSOCIATED WITH INDUCTION OF ALZHEIMER'S DISEASE
    (Nazarbayev University School of Medicine, 2024-04-26) Berikkara, Assel
    Background: Alzheimer’s disease represents the most prevalent form of neurocognitive decline. The key distinguishing pathological markers within the central nervous system involve the aggregation of senile plaques resulting from a two-step cleavage of the amyloid precursor protein by beta- and gamma-secretase enzymes sequentially. Previous studies have demonstrated a positive correlation between individuals who have mononucleosis due to EBV infection and their increased vulnerability to Alzheimer's disease. Hence, a new outlook on the disease etiology known as the "infectious hypothesis" has directed attention toward the Epstein-Barr virus (EBV), a double-stranded DNA virus, in terms of its potential contribution to plaque formation and inflammation associated with Alzheimer's disease. Methods: H4 neuroglioma and U118 glioblastoma cell lines were directly infected with EBV containing supernatant. The expression of APP and Tau mRNA was detected by qPCR. Protein levels were measured using ELISA with anti-APP antibodies, both before and after viral infection. Virus-free H4 and U118 cell lines were used as controls for comparative statistical analysis of mRNA and protein levels of the APP gene. Results: Infected U118 cell growth was maintained for more than 20 days, while H4 cells died out after the 7th day post-infection. qPCR results showed a consistent decrease in wild-type APP, APP-KPI, and APP-770 mRNA levels throughout the infection period, while Tau protein exhibited a statistically significant decrease in its expression level. In H4 cells, there was a decrease in WT APP and APP-KPI, while tau protein showed an enhanced mRNA level compared to the control. Conclusion: Direct EBV infection of glial cells resulted in alterations in the expression of Alzheimer's disease hallmark genes (WT APP, APP-770, APP-751, and Tau) in both H4 and U118 cell lines in a time-dependent manner.