Project No.2213

Primary Supervisor

Prof Jonathan Essex- University of Southampton

Co-Supervisor(s)

Prof Louise Serpell – University of Sussex

Prof Amrit Mudher – University of Southampton

Summary

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects 36 million people worldwide, and by 2050 more 115 million are predicted to have AD.

The pathology of AD results from the progressive accumulation of disease specific protein aggregates (called amyloid plaques and neurofibrillary tangles) in the brain and no disease modifying therapies exist. Tangles are made up of Tau protein monomers that misfold, self-assemble and accumulate, disrupting cellular function and are implicated in the pathology.

In this project, we will combine novel spectroscopic (Raman spectroscopy) and in silico techniques (Molecular Dynamics) to understand the structure-disease relationships in Tau. Previous work has shown that we can acquire the vibrational Raman spectra of tau oligomers and observe structural changes as fibrils form. Separately, we have demonstrated that we can calculate the electric fields, and hence the vibrational frequencies, of molecular probes in proteins in silico. Here we will combine experimental and in silico data to study tau aggregation in AD, specifically oligomer structure and evolution into larger fibrils. To confirm that simulation and spectroscopy can be combined and to determine the conformation of Tau seeds, the methodology will be developed and tested on carbonyl motifs present in two relevant hexapeptides VQIVYK (PHF6) and VQIINK (PHF6*). Both are essential for fibril formation in Tau and spontaneously aggregate.

Following refinement of computational models using calibration data, Raman spectra of hexapeptides as monomers, oligomers and fibrils will be acquired. The insight gained by simulations will help understand interactions and allow the development of in silico models of compound (drug) interactions with tau aggregates. This project will link experimental and simulation structural ensembles, allowing the mechanism of oligomer formation to be followed with molecular detail, giving vital insights into potential therapeutic interventions.