Professor Amritpal Mudher

The overarching aim of our research is to investigate the mechanisms that underpin tau-mediated dysfunction and degeneration in tauopathies such as Alzheimer’s disease and fronto-temporal dementia (see Mudher et al 2004, Mol Psychiatry, Cowan et al 2020 Acta Neuropathologica for early investigations). More recently these studies include projects to investigate propagation of tau pathology in vivo in Drosophila. Some of this work led to identification of disease-modifying tau-centred therapeutic targets (See Quriase et al 2013 Mol. Psychiatry). It has also raised interesting questions about the pathological significance of established tau aggregates such as soluble forms of tau, tau oligomers and tau filaments. More recently we are assessing whether tau-mediated axonal degeneration is wallerian in nature.

A related project investigates the cross talk between type-2 diabetes and Alzheimer’s disease. Using transgenic models and human tissue, the impact of an insulin resistant on tau phosphorylation and aggregation state are investigated. This will shed light on the mechanisms that underpin the cross talk between these two co-morbidities.

Another branch of research focuses on understanding how the neuronal cytoskeleton as well as cellular processes implicated in tau turnover, such as autophagic/proteosomal clearance, change with age. In parallel we seek to investigate how these changes contribute to development of Alzhiemer’s disease by studying their interaction with both tau and amyloid pathologies and phenotypes.

A major research area is a set of inter-disciplinary projects that utilise biophysical methodologies to study tau aggregation. Using label-free techniques such as AFM, Raman spectroscopic techniques and DLS, these projects aim to interrogate and characterise tau aggregates formed in vitro, in transgenic fly and mouse models of tauopathy as well as in brains of tauopathy patients. By generating unique spectral signatures for various disease associated forms of these proteins, we hope to use this technology to probe biological fluids for biomarkers of early disease.