(MRC DTP) The role of complement in the early stages of Alzheimer’s Disease

Alzheimer’s disease (AD) has grown to be the leading cause of death in the UK, and yet it stands alone amongst the UKs biggest killers as having no disease-modifying treatment. Despite numerous clinical trials aimed at reducing the levels of insoluble and toxic amyloid protein in the brain – a key feature of AD – little progress has been made and new approaches are urgently required.

We have recently completed a large screen of proteins in the human AD brain and shown that not only are multiple members of the complement pathway changing in their expression in AD, these changes appear to be seen early in the disease. Since complement activation in itself can prove toxic, and can further recruit damaging cellular immune responses, this represents a prime candidate for further study, with the eventual aim of targeting complement activation in the brain as a potential therapeutic approach.

The overall aim of this project is therefore to validate complement activation as a key early event in human AD. This will be done by measuring the levels of key complement proteins by a range of tools, including immunofluorescence microscopy and mass spectrometry, not only in patients with confirmed AD but also in patients at risk of AD, or with early but asymptomatic disease, to determine at what stage in the disease process complement levels change. This will be correlated with other disease features such the presence of amyloid or immune cell activation.

Since increased expression is not necessarily an indicator of increased activity, methods will also be developed to assess complement activation in tissue samples.

Finally, this project will also assess complement activation (and the timing thereof) in an animal model of AD, providing critical data for future projects where inhibitors of complement activation, which we are developing for a different disease as part of a separate project, could potentially be repurposed for use to slow or prevent the progression of AD.


https://www.research.manchester.ac.uk/portal/r.unwin.html
https://www.research.manchester.ac.uk/portal/catherine.lawrence.html
http://www.eye-tuebingen.de/clark/


Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships