Tauopathies are a group of heterogeneous dementias and movement disorders characterised by intracellular accumulations and hyperphosphorylation of the microtubule-associated protein Tau. The best known tauopathy is Alzheimer’s Disease, once thought to develop solely by the aggregation of β-amyloid into plaques. It is now understood to also be a result of the misfolding of Tau, alongside the aggregation of β-amyloid plaques. Neurodegeneration cannot be reversed, and the effects of these diseases can only currently be alleviated, not cured. With increases in technology and scientific capabilities, tauopathy research has exponentially grown and it is hoped that a treatment for neurodegenerative diseases will be developed. Tau typically plays a role in maintaining the stability of microtubules and axons in the neurons. When Tau becomes hyperphosphorylated, it loses its normal physiological function and aggregates into toxic neurofibrillary tangles, a hallmark of tauopathies. This work uses the larval neuromuscular junction of the fruit fly, Drosophila melanogaster¸ a well-established model system for studying tauopathies, to analyse two aspects of tauopathies. The first aim sought to compare the effects of overexpressing each of the six human isoforms. The results showed that UAS-hTau0N3R, UAS-hTau2N3R and UAS-hTau0N4R produced statistically significant changes in NMJ morphology, with a decrease in average bouton size, and that UAS-hTau0N3R was the only isoform to produce a significant change in average bouton number. These results were surprising and do not align with previous work which suggest that all Tau isoforms are equally toxic. The second aim was a proof
of principle study to see if co-expression of the synaptic proteins known as Neurexins could ameliorate the toxic effects of Tau. Neurexins are presynaptic cell adhesion proteins which alongside Neuroligins, their post-synaptic partners, promote and stabilise synapse formation. The effects of Neurexin expression on the Tau phenotypes was inconclusive, with the crosses designed to generate co-expression of Neurexin and Tau proving lethal. The implications of these results are discussed and suggestions for further experimental work proposed.