X-ray Spectromicroscopy Studies of Magnetic Iron Biominerals related to Alzheimer’s Disease

Lead Research Organisation: Keele University
Department Name: Inst for Science and Tech in Medicine

Abstract

This proposed project will utilise novel synchrotron x-ray techniques to investigate the origin and role of nanoscale biologically derived iron minerals together with peptide aggregates in Alzheimer's disease (AD). Recent research suggests that the formation of iron mineral deposits and the aggregation of the amyloid-beta peptide could be intimately linked with the development of the disease. Further, the development of magnetic iron minerals may help to provide early diagnosis due to their affect on magnetic resonance images (MRI). The project will build on some recent successful experiments performed by the applicants at the Swiss Light Source and Canadian Light Source facilities, and will utilise the strong track record of the applicants in the application of synchrotron techniques to the analysis of magnetic materials and biominerals. As the facilities required for these experiments do not yet exist within the UK, funding is requested for overseas travel for the principle investigator. This will enable him to perform further experiments, build collaborations with scientists at international synchrotron laboratories, and provide crucial on-site training for a PhD student involved in the project. Further to this, the expertise and technical achievements attained in the project could be translated to planned facilities that will become available at the Diamond Light Source laboratory in the next 3-4 years.

Planned Impact

Alzheimer's disease affects nearly half a million people in the UK alone and is the most common cause of dementia throughout the world. It is estimated that the annual cost of healthcare and treatments for dementia in the UK totals around £20 billion pounds. Alzheimer's is a progressive condition and the chances of prolonging life and improving the efficacy of treatments is greatly enhanced if diagnosis can be made early. Thus research into the causes and progression of the disease is essential and has the potential for huge impacts in the treatment of the disease.

The proposed project will apply an innovative use of x-ray synchrotron techniques that have previously been the realm of condensed matter physics, to study the links between beta-amyloid aggregation and iron biomineralization in Alzheimer's disease. This research will be truly multidisciplinary in nature and will therefore benefit a broad cross-section of academics in both the UK and overseas working in areas as diverse as biomaterials, physics, biochemistry and neuroscience.

In addition to academia, another key group that will ultimately benefit from the proposed research are general healthcare workers. This includes those in the public sector, such as NHS workers who will benefit from the subsequent development of targeted therapeutics for the treatment of Alzheimer's and other neurodegenerative diseases, as well as the potential advances in early diagnosis that could be made due to a better understanding of magnetic biominerals in the brain. It also includes the private sector who could exploit a better understanding of the progression of the disease in order to develop new pharmaceuticals, treatments and diagnostic equipment.

Further to the above groups the general public would greatly benefit from the eventual development of the above treatments, therapies, and early diagnosis which could have a significant impact on slowing and perhaps ultimately halting the progression of the disease. In addition to promoting health and wellbeing, such improvements in treatments are likely to impact on the economic costs of the disease to the UK and global sectors.

Publications

10 25 50
 
Description The EPSRC overseas travel grant has enabled us to perform scanning transmission x-ray microscopy (SXM) measurements at international facilities, generating significant new knowledge on the interaction of iron and the amyloid-beta peptide, with relation to the origins and progression of Alzheimer's disease. In particular we have shown the following: (i) that the amyloid-beta peptide can reduce biologically relevant iron (III) minerals including ferrihydrite, forming pure Fe(II) minerals and magnetite; (ii) that similar reduced iron minerals exist in transgenic mouse cortical tissue that are associated with regions of disease pathology such as amyloid plaques, and (iii) that regions of amyloid-beta and iron are correlated at the nanoscale level and that plaque regions appear to contain a composite iron-amyloid material. These results have led to the publication of two journal papers, the submission of a further journal paper, and additional magazine/on-line articles and media work.

As part of this project we successfully translated x-ray synchrotron techniques from the realm of materials physics to biomedical research areas. This would not have been possible without access to overseas SXM facilities at the Canadian Light Source and the Swiss Light Source. The success of our work has also now led to the award of facilities time at the Advanced Light Source (Berkeley, USA), where our proposal scored in the top 2% of all submissions. These ongoing experiments will develop further the techniques in order to explore human tissue samples. Further to this, we have established a significant new collaboration with facilities staff at the new SXM beamline at the Diamond Light source, thus bringing the expertise we have gained through international collaboration, home to the UK. We have also recently performed some of the first commissioning experiments on the new Diamond beamline (I08), and have ongoing experiments planned there in the coming year.

Our results have opened up new avenues of research by suggesting that the role of iron in Alzheimer's disease pathology may be far more significant than originally thought. Further, our in vitro studies have revealed possible mechanisms for the production of the reduced iron minerals found in Alzheimer's tissue. Further work will look at possible targets for amyloid reduction, such as the dysregulation of the ferritin protein. In addition to journal publications, the EPSRC overseas travel grant significantly contributed to the PhD training of a student, James Everett, who has now passed his PhD and has submitted a Fellowship application to the Alzheimer's Society, pursing some of the themes discussed above.
Exploitation Route We believe the results from this project could lead to a step change in current thinking of how iron is linked to AD and other related neurodegenerative disorders. Our findings will thus be of great interest to researchers working on the origins, treatment and MRI imaging of these conditions. Further, the application of the x-ray techniques to new areas such as biomedicine and disease pathology will find a wide audience, whilst the aspects of our work concerning iron biomineralisation are likely to be of particular interest to microbiologists.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Other

 
Description In addition to academic impact we have produced on-line research articles for the general public, and have interacted with the media to disseminate the results as widely as possible. We have also presented the themes of the research to the general public at Open Days. In 2016, our research also become relevant to the debate on air pollution caused by diesel engines in cars (impact - economic; societal, policy and public services). Specifically, research publish in the journal PNAS suggested that some of the nanoparticulate iron minerals found in the brain could come from diesel exhaust fumes. We were asked to provide expert comment on this work prior to the lifting of the media embargo.
Sector Chemicals,Education,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Transport
Impact Types Cultural,Societal,Economic,Policy & public services

 
Description Diamond Light Source Programme Access - Long Term Research
Amount £0 (GBP)
Organisation Diamond Light Source 
Sector Private
Country United Kingdom
Start 04/2017 
End 03/2019
 
Description EPSRC Responsive Mode
Amount £755,759 (GBP)
Funding ID EP/N033140/1; EP/N033191/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 01/2020
 
Description Article in research news publication 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Colleagues working in the area of synchrotron research were made aware of this research and in particular the new application of specialized techniques to bio-medical sciences.

Interest in this area from the x-ray synchrotron community was increased.
Year(s) Of Engagement Activity 2014
 
Description Harwell Campus Open Day 2015 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact My colleagues and I presented an exhibition stand on the role of iron in neurodegenerative diseases at the Harwell Campus Open Day on Saturday 11 July 2015. We presented our work, including the synchrotron results from this award, and held discussions with members of the public and school students.
Year(s) Of Engagement Activity 2015
URL http://harwellcampus.com/events/open-days/public-day/
 
Description Media interest (amyloid-iron research) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact The press release was picked up by international on-line medical websites and magazine editorials, as well as by regional newspapers. An interview on the topic was given to BBC local radio.

The journal papers associated with the press release received great interest from the research community. Notably one of the papers (published in Royal Society Interface) was listed as the 3rd most read article in the journal for the publication month, and stayed in the top 20 for the subsequent 3 months after publication.
Year(s) Of Engagement Activity 2014
 
Description On-line article on news feed 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The article generated interest in our research from the public as well as research community.

Requests for follow up articles were made, in particular for industry based research opportunities.
Year(s) Of Engagement Activity 2014
URL http://www.diamond.ac.uk/Home/News/LatestNews/27-03-14.html