Our work focuses on investigating the molecular mechanisms underlying the development and progression of neurodegenerative diseases such as Alzheimer’s disease and related dementias. We use a diverse range of model systems to examine key proteins and pathways implicated in neurodegeneration and to conduct pre-clinical studies with potential therapeutics.
1. Abnormal tau processing and altered tau function in dementias.
We have a particular interest in tau protein modifications and how these alter tau function and contribute to the development of disease. We, and our collaborators have demonstrated important roles for the tau kinases cdk5, GSK-3, c-Abl and Fyn in Alzheimer’s disease and related tauopathies. We have investigated the role of tau phosphorylation and cleavage on tau function and tau-associated neurotoxicity, and have conducted pre-clinical studies using tau protein modifiers.
2. Neuron-glial interactions in Alzheimer’s disease.
We have shown that minocycline, an anti-inflammatory agent, is neuroprotective in models of Alzheimer’s disease, acting to reduce astrocyte activation and suppress the release of key pro-inflammatory mediators from these glial cells. We have also found that astrocytes play a key role in mediating Aβ-induced neurotoxicity and Aβ-induced tau phosphorylation in cortical neurons. We are currently investigating the role of astrocytes in mediating tau-directed synaptotoxicity with the aim of determining novel druggable targets.
3. Mechanisms underlying tau release and propagation.
In collaboration with Professor Diane Hanger and Dr Amy Pooler, we reported that neuronal activity stimulates tau release from neurons. We have since used organotypic brain slice cultures to demonstrate that there may be differential mechanisms governing the release of soluble physiological tau and disease associated pathological species of tau. We are continuing to use brain slice cultures and other neuronal cell systems to elucidate the mechanisms involved in these processes. We also use in vivo models of tau propagation based on mice expressing wild-type human tau.
Major collaborators within the IoP include:
Dr Diane Hanger
Professor Chris Miller
Professor Peter Giese
Our work is currently funded by the BBSRC, MRC, MedImmune/AstraZeneca and Alzheimer’s Research UK