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Investigating the in vivo targets and mechanism of action of a toxic acetylcholinesterase-derived peptide upregulated in Alzheimer’s disease.

  • Full or part time
  • Application Deadline
    Monday, January 06, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Project description
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is characterised by the deposition and accumulation of amyloid beta plaques and phosphorylated tau filaments in the brain, the latter correlating with the onset of symptoms. However, the widespread distribution of both amyloid and tau accumulations throughout the brain does not account for the specific identity and deep subcortical location of the primarily vulnerable neurons. The vast majority of AD cases are sporadic and the basic mechanism driving the continuing process of neurodegeneration in selectively vulnerable cells, has not been identified.

Our industrial partner, Neuro-Bio has recently determined that a novel 14-residue peptide (‘T14’) cleaved from the protein acetylcholinesterase which has conspicuous sequence homology to amyloid beta, is toxic and is upregulated in AD. This has been demonstrated using a proprietary antibody in a mouse model of AD, post-mortem brain tissue and in CSF and plasma from AD patients. T14 is present in all vulnerable cell populations irrespective of their neurotransmitter type and it drives the production of both amyloid and hyperphosphorylated tau. Strikingly, these effects can be inhibited by a novel prototype drug (NBP-14), a cyclised form of T14 peptide developed at Neuro-Bio. These findings potentially place T14 upstream of amyloid and tau, however, a mechanistic understanding of the role of T14 in health and disease is lacking.

Objectives

This project aims to understand the mechanism of T14 peptide toxicity and how elevated levels contribute to neurodegeneration in AD. This project will uncover how T14 peptide is produced, what it targets in vivo, how this perturbs neurons and if chronic changes are evident in clinical samples. In addition, the potential of NBP-14 as a therapeutic will be investigated in this project.
Training
The student will work at the interface of academia and industry in an established team of investigators with expertise in proteomics and neuroscience and will benefit from available reagents, assays, ex-vivo AD models and clinical samples. This project will employ a range of mass spectrometry-based proteomic strategies to identify proteases that generate T14 peptide, identify proteins that interact with T14 peptide, profile proteomes in response to T14/NBP-14 treatment and clinical proteomic approaches to measure biomarkers in patient samples. Training will also be provided in mammalian cell culture, immunoprecipitation, western blotting, immunofluorescence microscopy and calcium imaging.

You will be supervised by Dr Mark Collins at the Department of Biomedical Science, https://www.sheffield.ac.uk/bms/research/collins and by Baroness Professor Susan Greenfield at Neuro Bio Ltd. Oxford (https://neuro-bio.com/). This project will include an industrial placement of at least three months at Neuro Bio Ltd.
Interested applicants should contact Dr Collins to discuss the project further ().

Science Graduate School
As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more.

Funding Notes

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First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link: View Website
All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information.

References

References

Brai E, Stuart S, Badin AS & Greenfield SA. (2017) “A novel ex-vivo model to investigate the underlying mechanism in Alzheimer’s disease.” Front. Cell. Neurosci. Doi: 10.3389/fncel.2017.00291.

Garcia-Ratés, S, Morrill, P, Tu, H, Pottiez, G, Badin, A-S, Tormo-Garcia, C, Heffner, C, Coen, CW & Greenfield, SA. (2016) (I) “Pharmacological profiling of a novel modulator of the α7 nicotinic receptor: Blockade of a toxic acetylcholinesterase-derived peptide increased in Alzheimer brains.” Neuropharmacology, vol 105, pp. 487-499.

Fernández E, Collins MO et al. Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence. Cell Rep. 2017 Oct 17;21(3):679-691.
Hosp F, Mann M. A Primer on Concepts and Applications of Proteomics in Neuroscience. Neuron. 2017 Nov 1;96(3):558-571.

How good is research at University of Sheffield in Biological Sciences?

FTE Category A staff submitted: 44.90

Research output data provided by the Research Excellence Framework (REF)

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