Good Vibrations: Using Raman Spectroscopy and Molecular Dynamics to Shed Light on the Aggregation Mechanism of Tau in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder that affects 36 million people worldwide.
Owing to an increased life expectancy and aging populations, by 2050 more 115 million are predicted to have AD. The pathology of AD results from the progressive accumulation of 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 in disease. In this project, we will develop novel spectroscopic and in silico tools to understand the structure-pathogenicity relationships in Tau protein that determine its disease-related misfolding, subsequent aggregation and spread of disease. In this way we will pave the way for disease-modifying therapies. In previous work, we have demonstrated that we can acquire the vibrational Raman spectra of tau oligomers, and demonstrated time evolution as fibrils form. Separately, we have demonstrated that we can calculate the electric fields, and hence the vibrational frequencies, of molecular probes in proteins. Here we will combine novel spectroscopic and molecular simulation studies, to study peptide aggregation in general, and tau oligomer structure and evolution into larger fibrils, in particular. 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 two relevant hexapeptides VQIVYK (PHF6) and VQIINK (PHF6*). Both are essential for fibril formation in Tau and spontaneously aggregate. Spectra will be derived using our previously published Raman approach. Advanced simulation techniques will be used to characterise the kinetic and thermodynamic parameters of peptide aggregate formation. Advanced polarisable force fields will be used to calculate vibrational spectra. Following refinement of computational models using calibration data, Raman spectra of hexapeptides as monomers,...