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MRC DiMeN Doctoral Training Partnership: Investigating the in vivo targets and mechanism of action of a toxic acetylcholinesterase-derived peptide upregulated in Alzheimer’s disease


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 ().


Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

iCASE Award: Industrial partnership project

Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.

Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

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.

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