Alzheimer's disease is characterized by the presence of amyloid plaques, made up primarily of Aϐ peptides, and neurofibrillary tangles, containing hyperphosphorylated tau. Aϐ is generated by sequential proteolysis of the amyloid precursor protein (APP) by beta and gamma secretases. The leading hypothesis of Alzheimer's disease pathogenesis is the amyloid cascade hypothesis, which suggests that amyloid is central to the disease process. However, tau pathology correlates more closely with cognitive dysfunction and follows a predictable anatomical course through the brain. We hypothesize that if Aϐ is upstream of tau pathology and tau pathology follows this predictable course through the brain, Aϐ production may also propagate through the brain in an anatomical fashion. In order to investigate this possibility, we examined two broad cellular processes induced in cells when exposed to Aϐ, p53-dependent apoptosis and cell cycle activation. We report that p53-dependent apoptosis is associated with a decrease in the Aϐ and sAPP-alpha and an increase in an alternative, caspase-cleaved fragment of APP, resulting from an apparent cleavage in the near extracellular domain of APP. Mitosis is associated with the phosphorylation of both tau and APP, and increased production of Aϐ. Our results indicate that while p53-dependent apoptosis is not associated with increased amyloidogenesis, cell cycle activation increases Aϐ production and may play a role in disease propagation. Together, these findings suggest various treatment approaches, including cell cycle inhibition and disruption of APP endocytosis, which may decrease amyloidogenic processing. Continued research into these potential approaches, coupled with earlier detection of the disease process, could lead to promising treatments for Alzheimer's disease.
| Identifer | oai:union.ndltd.org:USF/oai:scholarcommons.usf.edu:etd-5683 |
| Date | 01 January 2013 |
| Creators | Fiorelli, Tina N. |
| Publisher | Scholar Commons |
| Source Sets | University of South Flordia |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Graduate Theses and Dissertations |
| Rights | default |
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