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MRC DiMeN Doctoral Training Partnership: Neuroinflammation in Alzheimer’s disease: what is the role of amyloid-beta fibril structure?


MRC DiMeN Doctoral Training Partnership

Leeds United Kingdom Biochemistry Biophysics Cell Biology Immunology Molecular Biology Neurology Neuroscience Pathology Structural Biology

About the Project

This project will explore the role of amyloid-beta fibril structure in triggering neuroinflammation in Alzheimer’s disease.  

Alzheimer’s disease is the most common form of dementia and affects millions worldwide. The mechanisms of neurodegeneration in Alzheimer’s are poorly understood, hindering the development of much needed treatments.  Amyloid plaques and neuroinflammation are hallmarks of Alzheimer’s disease. Fibrils, rope-like fibres, formed by amyloid-beta are the principal component of the amyloid plaques. Amyloid-beta can however assemble into multiple different fibril types, known as polymorphs, each of which has a distinctive molecular structure.  Crucially rapidly progressing Alzheimer’s disease is associated with an increased number of amyloid-beta fibril polymorphs.  Moreover, early onset familial mutants of amyloid-beta assemble into fibrils which have different molecular structures to those formed the wild type sequence. Yet, despite its central role in Alzheimer’s pathology, little is known about how this structural polymorphism affects the biological properties of amyloid-beta fibrils.

Amyloid-beta fibrils can activate the brain’s resident immune cells, microglia, triggering a damaging inflammatory response.  This project will test whether the microglial inflammatory response is differentially activated by the polymorphic variants of amyloid-beta fibrils. Amyloid-beta fibrils will be produced from the wild type sequence and from familial mutants associated with Alzheimer’s disease, generating fibril polymorphs that have well-defined, but distinctive molecular structures.  The activation of microglia will be investigated by performing side by side comparisons of the effect of the amyloid-beta fibril polymorphs on fibril uptake, proinflammatory signalling, cytokine secretion, microglial morphology and the expression of molecules that activate T-cell mediated immunity.  

This PhD will be a collaborative project in the Astbury Centre for Structural Biology, University of Leeds between the research groups of Dr Eric Hewitt and Professor Sheena Radford FRS OBE.  The project will provide training in interdisciplinary science, with the PhD student developing expertise at the interface of the molecular (protein chemistry, structural biology and biophysics) and cellular (immunology and cell biology) biosciences.  

Further information about the supervisors’ research can be found on their websites:

https://biologicalsciences.leeds.ac.uk/biological-sciences/staff/127/professor-sheena-radford

https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/84/dr-eric-hewitt

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 and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

Brown M, Radford SE and Hewitt EW (2020). Modulation of β-amyloid fibril formation in Alzheimer’s disease by microglia and infection. Front. Mol. Neurosci. 13:609073.
Karamanos TK, Matthew MP, Calabrese AN, Goodchild SC, Cawood EC, Thompson GS, Kalverda AP, Hewitt EW and Radford SE (2019). Structural Mapping of Oligomeric Intermediates in an Amyloid Assembly Pathway eLife 8:e46574
Iadanza MG, Jackson MP, Hewitt EW, Ranson NA, Radford SE. (2018) A new era for understanding amyloid structures and disease. Nat Rev Mol Cell Biol. 19:755-773.

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