Alzheimer’s disease (AD) is characterised pathologically by the deposition of amyloid-β in extracellular amyloid plaques and of tau in neurofibrillary tangles. Plaques and tangles spread through the brain during the progression of AD. The neurofibrillary tangles of tau initially appear in the entorhinal cortex and hippocampus, before the expansion of tau pathology into neighbouring areas. This spread of tau pathology is a result of tau ’transmission’ from one cell to another. However, the molecular and cellular mechanisms for this cell-to-cell transmission of tau are not known. Further insight into tau transmission may provide opportunities for therapeutic intervention in AD.
This project will seek to address key questions regarding the transmission of tau:
1) What is the form of tau that is transferred between cells? Is it phosphorylated, truncated or post-translationally modified in another way? Is it monomeric or aggregated (oligomers, fibrils) of tau that are transmitted?
2) Which cell types are involved? Neurons, microglia, astrocytes? How do the interactions between these different cells contribute to tau propagation through the brain?
3) Is tau released into solution or in membrane-bound vesicles such as exosomes? Do risk factors for AD, such as hypoxia, promote tau release from donor cells?
4) What is the mechanism of uptake of the tau into the recipient cell? Which cell surface receptors are involved and can these be blocked to prevent uptake?
The successful candidate will use a range of biophysical, biochemical, molecular biological and cell biological techniques to address these fundamental questions, with a focus on using human induced pluripotent stem cell (iPSC) models of differentiated neurons and glia in co-culture. Training will be provided in a wide range of experimental techniques including: SDS PAGE and western blotting, enzyme assays, site-directed mutagenesis, siRNA and confocal immunofluorescence microscopy.
Applicants are expected to hold (or about to obtain) a minimum upper second class degree in neuroscience, cell biology, biochemistry, pharmacology, physiology or biomedical sciences. A Masters degree or at least 2 months of relevant laboratory experience would be an advantage.
This 3-year full-time PhD is open to candidates able to provide evidence of self-arranged funding/ sponsorship. Fee rates for this project, due to commence from September 2016 onwards, are:
UK/EU nationals: £14, 000*
Non-EU nationals: £27, 500
Please direct applications in the following format to Professor Nigel Hooper ([email protected]
• Academic CV
• Official academic transcripts
• Contact details for two suitable referees
• A personal statement (750 words maximum) outlining your suitability for the study, what you hope to achieve from the PhD and your research experience to date
• Evidence of funding
Any enquiries relating to the project and/or suitability should be directed to Professor Hooper. Applications are invited on an on-going basis but early expression of interest is encouraged.
Vardy, E.L.R.C., Kellett, K.A.B., Cocklin, S.L. & Hooper, N.M. (2011) Neurodegenerative Dis. 9, 31-37. Alkaline phosphatase is increased in both brain and plasma in Alzheimer’s disease.
Watt, N.T., Taylor, D.R., Kerrigan, T.L., Griffiths, H.H., Rushworth, J.V., Whitehouse, I.J. & Hooper, N.M. (2012) Nature Communications, 3, doi:10.1038/ncomms2135. Prion protein facilitates uptake of zinc into neuronal cells.
Rushworth, J.V., Griffiths, H.H., Watt, N.T. & Hooper, N.M. (2013) J. Biol. Chem. 288, 8935-8951. Prion protein-mediated neurotoxicity of amyloid-β oligomers requires lipid rafts and the transmembrane LRP1.
Whitehouse, I.J., Miners, J.S., Glennon, E.B., Kehoe, P.G., Love, S., Kellett, K.A. & Hooper, N.M. (2013) PLoS ONE 8:e59554. Prion protein is decreased in Alzheimer’s brain and inversely correlates with BACE1 activity, amyloid-β levels and Braak stage.
Hettiarachchi, N., Dallas, M., Al-Owais, M., Griffiths, H., Hooper, N.M., Scragg, J., Boyle, J. & Peers, C. (2014) Cell Death Dis. 5, e1569. Heme oxygenase-1 protects against Alzheimer's amyloid-beta(1-42)-induced toxicity via carbon monoxide production.