| Popis: |
A central event in Alzheimer's disease is the accumulation of amyloid [beta] (A[beta]) peptides generated by the proteolytic cleavage of the amyloid precursor protein (APP). APP overexpression leads to increased A[beta] generation and Alzheimer's disease in humans and altered neuronal migration and increased long term depression in mice. Conversely, reduction of APP expression results in a decreased A[beta] levels in mice as well as impaired learning and memory and decreased numbers of dendritic spines. Together these findings indicate that therapeutic interventions that aim to restore APP and A[beta] levels must do so within an ideal range. To better understand the effects of modulating APP levels, we explored the mechanisms regulating APP expression focusing on post-transcriptional regulation. Such regulation can be mediated by RNA regulatory elements such as guanine quadruplexes (G-quadruplexes), non-canonical structured RNA motifs that affect RNA stability and translation. Presented in this thesis, we identified the G-quadruplex as a novel endogenous regulator of APP expression within the APP mRNA in its 3'untranslated region at residues 3008-3027 (NM_201414.2). This sequence exhibited characteristics of a parallel G-quadruplex structure as revealed by circular dichroism spectrophotometry. Further, as with other G-quadruplexes, the formation of this structure was dependent on the presence of potassium concentration. Moreover, we present preliminary data demonstrating that FMRP and FXR2P bind to the APP G-quadruplex sequence and regulates it expression. |
