A central event in the pathogenesis of Alzheimer's disease (AD) is the regulated intramembraneous proteolysis of the amyloid precursor protein (APP) that produces the amyloidogenic A? peptide. Important to AD pathology is the increased levels of APP, which invariably causes disease. There are several therapeutic strategies that involve targeting A? generation by inhibiting the secretases that cleave APP;however, the regulatory mechanisms controlling APP proteolysis and A? generation are not completely understood. We have made a novel discovery that addresses a possible mechanism to understand how APP gene expression can be regulated and may offer therapeutic insight. We have identified the presence of a guanine quadruplex (G- quadruplex) sequence located within the 3'untranslated region (UTR) of APP, which we confirmed through the use of circular dichroism spectrophotometry. Using a variety of molecular techniques to characterize the effects of the G-quadruplex on gene expression, we found that the G-quadruplex negatively regulates APP gene expression. G-quadruplexes have been reported to regulate the translation of mRNAs by inhibiting ribosomal elongation, interacting with RNA Binding Proteins, and targeting mRNAs for localization in neurons. The proposed research is aimed at characterizing a mechanism by which the G-quadruplex regulates APP gene expression by determining if the G-quadruplex affects miRNA-mediated regulation of APP expression, the binding of RNA Binding Proteins, and localization of APP mRNA. This connection may be important to AD pathogenesis since increased levels of APP cause AD. The results from this work will help us to better understand how APP gene expression is regulated and will provide a novel insight into the involvement of APP in AD pathogenesis, which may provide novel therapeutic targets and strategies for AD treatment.
Alzheimer's disease is becoming more prevalent in the U.S. and there are currently no drugs that treat the underlying causes of the disease. Here we are proposing to investigate a novel approach to potentially treat this disease. We are seeking to understand how levels of a gene, central to the development of Alzheimer's disease, are regulated.