MicroRNAs as Novel Therapeutics and Diagnostics in Alzheimer’s Disease

Advances in therapeutics for Alzheimer’s disease (AD) has stagnated for almost 2 decades and there is an increasing interest in deviating from standard targets and strategies which have repeatedly failed in clinical trials. It is a widespread belief in the field that targeting multiple components of AD pathology and applying treatments at earlier stages of AD are key to the development of a cure. Approaches which the short non-coding molecules MicroRNAs (miRNAs) could greatly aid. Within this thesis, I look to utilise AD-related changes in miRNA expression as biomarkers of AD pathology and apply them to the development of a minimally invasive diagnostic tests to aid in the identification of AD and its prodromal stages utilising distinct changes in blood plasma and tear fluid. My profiling study of the miRNA composition in blood identified a distinct expression pattern in AD and MCI subjects with elevated miR-206, Let-7b. We established a precedent for the application of the validated miRNA signature of miR-206 in plasma within an electrochemical detection system, providing a costeffective, point-of-care diagnostic tool. The tear fluid expression profile in AD and MCI establishes a precedent of altered miRNA levels in tear fluid as a novel non-invasive source of miRNA based biomarkers in AD. I characterised Argonaute-2 bound miRNAs in VLW mice to provide a database of miRNA activity changes in a mouse model of tauopathy which can aid the elucidation of Tau’s role in driving miRNA changes in AD and identified a plethora of key miRNAs which undergo distinct alterations in response to aberrant Tau pathology (miR-99a, miR-101, miR-134 and miR-125b). We interrogate the role of miR-22 in regulating neurogenesis in models of Temporal lobe epilepsy, identifying important functions in regulating the morphogenesis of newly-formed neurons and suppressing aberrant neurogenesis with significant implications in AD. The findings in this thesis represent an advancement in the current knowledge of miRNAs in neurological diseases and can provide significant aid to future work in both clinical and research fields targeting earlier stages of AD or targeting miRNA changes in AD as a therapeutic intervention.