Date of Award

2011

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Denah M. Appelt, PhD

Second Advisor

Brian Balin, PhD

Third Advisor

Susan T. Hingley, PhD

Fourth Advisor

Marcus Bell, PhD

Abstract

Dysfunctions in cellular mechanisms such as apoptosis and autophagy have been implicated in the neurodegeneration associated with Alzheimer’s disease (AD). Autophagy in AD pathogenesis has been linked to the endosomal-lysosomal system, which has been shown to play a role in amyloid processing. Studies have suggested that apoptosis may contribute to the neuronal cell loss observed in AD; however, there is no evidence of the apoptotic process leading to terminal completion. Aβ1-42 has been shown to induce apoptosis in neurons and may be an initiating factor in AD. Our previous studies demonstrated that neurons infected with C. pneumoniae are resistant to apoptosis, and that Aβ1-42 was increased by the infection. Additionally, studies have demonstrated the interactions of several pathogens on the autophagic pathway. The focus of the current studies was to determine if there is a relationship between the molecular mechanisms interconnecting autophagy and apoptosis following C. pneumoniae infection in neuronal cells that could lead to the pathologies observed in AD. SKNMC neuronal cells obtained from ATCC were infected with the AR39 strain of C. pneumoniae at an MOI=1 for 24hrs to 72hrs and were analyzed using Real-time PCR arrays from SABiosciences specific for autophagy and apoptosis markers. At 24hrs, neuronal cells infected with C. pneumoniae resulted in down-regulation of apoptosis and autophagy gene regulation. Neuronal cells infected at 72hrs with C. pneumoniae up-regulated the expression of several genes associated with autophagy and apoptosis. For example, BECN1 and ATG4C, both prominent genes in the autophagy pathway were 3.66 to 25.77 fold down-regulated at 24hrs and increased 1.53 to 1.73 fold 72hrs post-infection, iv respectively. Similarly, apoptosis gene expression such as that for BAK1 was increased from -1.15 fold at 24hrs to 2.09 fold at 72hrs post-infection. Our data suggest that C. pneumoniae exerts a control over changes in gene regulation affecting the apoptotic and autophagic processes in neuronal cells. As both autophagic and apoptosis dysfunction have been observed in AD, the impairment of these normal cellular processes by a pathogen such as C. pneumoniae may contribute to the neuropathology seen in AD.

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