Imperial College London Featured PhD Programmes
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Characterisation of the neuronal receptor for soluble amyloid precursor protein: a route to new therapeutic targets for Alzheimer’s disease


Project Description

Alzheimer’s disease (AD) is the commonest form of dementia for which currently there is no means of stopping or even slowing the disease. The major symptom of Alzheimer’s disease is cognitive dysfunction, often seen as a loss of memory, caused by changes in nerve cell function. The alpha-secretase-cleaved soluble form of the amyloid precursor protein (sAPPalpha) has neuroprotective properties and can rescue the structural, electrophysiological and behavioural deficits in AD model mice by enhancing synaptic activity. These effects of sAPPalpha are mediated through interaction with an unknown receptor on the surface of neurons. Our preliminary data indicate that sAPPalpha binds to a receptor on the surface of human induced-pluripotent stem cell (iPSC)-derived neurons, increases the expression of synaptic proteins and stimulates N-methyl-D-aspartate (NMDAR)-dependent membrane depolarisation, thereby enhancing synaptic activity. We hypothesise that identification and characterisation of the neuronal receptor for sAPPalpha and the downstream signalling pathways linking to increases in synaptic activity, will provide new information on the molecular and cellular mechanisms underpinning the neuroprotective properties of sAPPalpha. The objectives of this project are to: 1) identify the receptor(s) for sAPPalpha on human iPSC-derived neurons using chemical cross-linking and mass spectrometry identification in conjunction with bioinformatics; 2) confirm the ability of the receptor to mediate the effects of sAPPalpha on synaptic protein expression and NMDAR-dependent synaptic activity in neurons using a combination of genetic and pharmacological approaches, and determine whether the expression of the receptor is altered in AD brain; and 3) determine the neuronal sAPPalpha induced signalling pathways that link to changes in synaptic activity using mass cytometry. The information gained will further our understanding of the role of sAPPalpha in brain function and will open the way to important new pharmacological approaches to mimic sAPPalpha activity as a potential therapeutic approach for AD.

Training/techniques to be provided:
The student will receive training in biochemistry and cell biology, including the growth and differentiation of induced pluripotent stem cells, immunofluorescence microscopy, receptor identification, mass spectrometry, proteomics and bioinformatics analyses.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (B.Sc. or equivalent) in a related area / subject (e.g. biochemistry, cell biology, neuroscience) and preferably a master degree in a related area.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Andrew, R. J., Fisher, K., Heesom, K.J., Kellett, K.A.B. & Hooper, N.M. (2019) J. Neurochem. 149, 399-412. Quantitative interaction proteomics reveals differences in the interactomes of amyloid precursor protein isoforms.

Jarosz-Griffiths, H.H., Corbett, N.J., Rowland, H.A., Fisher, K., Jones, A.C., Baron, J., Howell, G.J., Cowley, S.A., Chintawar, S., Cader, M.Z., Kellett, K.A.B. & Hooper, N.M. (2019) J. Biol. Chem. 294, 7085-7097. Proteolytic shedding of the prion protein via activation of metallopeptidase ADAM10 reduces cellular binding and toxicity of amyloid-β oligomers.

Horton, E.R., Byron, A., Askari, J.A., Ng, D.H.J., Millon-Frémillon, A., Robertson, J., Koper, E.J., Paul, N.R., Warwood, S., Knight, D., Humphries, J.D. & Humphries, M.J. (2015) Nature Cell Biol. 17: 1577-1587. Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly.

Horton, E.R., Humphries, J.D., Stutchbury, B., Jacquemet, G., Ballestrem, C., Barry, S.T. & Humphries, M.J. (2016) J. Cell Biol. 212: 349-364. Modulation of FAK and Src adhesion signaling occurs independently of adhesion complex composition.

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