University of Exeter
Deciphering cell-type specific effects of P2X7R antagonism on tauopathy ex vivo
P2X7R is a receptor that is predominantly expressed by non-neuronal cells in the brain. P2X7R levels are increased in AD and in tauopathies which accumulate modified forms of tau protein in the brain.
Recently, blocking the P2X7R receptor was found to reduce some abnormal forms of tau protein in mice that model aspects of tauopathies. However, it is poorly understood how P2X7R blockade in non-neuronal cells affects tau protein in neurons. In fact, there are disagreements about which cell types express P2X7R.
We used a sensitive approach to show that P2X7R is expressed in two types of non-neuronal cell in Alzheimer’s brain – astrocytes and microglia. We also showed effects of blocking P2X7R on tau aggregates in a slice culture model. These data lead us to speculate that P2X7R affects specific functions of the non-neuronal cells that allows them to interact with neurons to limit tau aggregation. Here, we aim to progress this work by determining which cell type mediates the beneficial effects of P2X7R blockade on tau, if P2X7R specifically affects tau aggregates, and the precise pathways involved.
We will use cultures of brain slices in which aspects of tauopathy are induced and specifically knockdown P2X7R in astrocytes and microglia to determine the cell type involved. We will use a sensitive long-term imaging approach to examine tau aggregate load upon P2X7R blockade.
Based on the data from these two sets of experiments, we aim to delineate the precise signalling pathways involved. These data will be of benefit to dementia researchers who are investigating similar pathways, and we hope that they will provide important information to those seeking to develop P2X7R-directed therapies.
This project is a collaboration between the University of Exeter, King’s College London (Dr Maria Jimenez-Sanchez) and University College London (Dr Cara Croft) and offers training opportunities at the London universities.
Applicants for this studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in neuroscience or a related discipline. Should these criteria not be met, applicants may be considered who have achieved a minimum ‘merit’ classification at MSc level in a relevant subject. Prior laboratory experience is desired, but not essential.
If English is not your first language you will need to meet the required level (Profile B) as per our guidance at https://www.exeter.ac.uk/pg-research/apply/english/
The closing date for applications is midnight on Friday 28th April 2023.
Interviews will be held virtually / on the University of Exeter St Luke’s Campus in the week commencing Monday 22nd May (TBC).
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