UNDERSTANDING THE PATHOLOGICAL EFFECTS OF EXOGENOUS MONOMERIC TAU PROTEIN AND THE DEVELOPMENT OF NOVEL TREATMENTS FOR ALZHEIMER’S DISEASE

Microtubule-associated protein tau (tau) is known to play a role in Alzheimer’s disease (AD) through pathways resulting in the gradual formation of neurofibrillary tangles. The uptake of monomeric tau from the extracellular medium, and its aggregation at low pH inside of neurons has previously been shown by the group, but any pathophysiological effects of this aggregation remain unclear. Tau pathology has also been shown to be dependent upon synaptic activity, which hints to the role of neuronal activity in the pathway leading to toxicity. Synaptic impairment followed by synapse loss are thought to be the first points of pathology that are seen during AD and result in symptoms of memory loss. This project aims to better understand the pathway through which aggregation of monomeric tau at low pH inside of endolysosomal compartments relates to pathology including impairment to synaptic function at the earliest stages of cytotoxicity. Through better understanding the pathways to aggregation and synaptic impairment, better therapeutic targets can be discovered. Alongside understanding tau pathology, this project aims to rescue symptoms by developing novel methods of treatment based on immunotherapies and neural stem cell prosthetics. Through this project, a novel electrophysiological phenotype has been found. The uptake of monomeric tau taken into neurons results in an activity-dependent depression of synaptic transmission. The mechanisms through which this pathology occurs have been explored through studies investigating the relationship of tau aggregation to calcium ion concentration and different cell stimulation mechanisms. Technology including microfluidic culture chips and microelectrode arrays have been developed to further identify how tau protein affects spontaneous activity and evoked responses of neurons. Novel therapeutic methods including metal organic frameworks grafted with immunotherapy and biofunctionalised scaffolds for enhanced neural stem cell implantation have been developed. These may prove beneficial for early and late stage treatments of Alzheimer’s disease