Nanoscale metallomics and mineralization: advanced spectro-microscopy determination of the role of iron and calcium in Alzheimer's disease
Lead Research Organisation:
University of Warwick
Department Name: Sch of Engineering
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Organisations
Publications
Everett J
(2021)
Biogenic metallic elements in the human brain?
in Science advances
Everett J
(2021)
Nanoscale chemical speciation of ß-amyloid/iron aggregates using soft X-ray spectromicroscopy
in Inorganic Chemistry Frontiers
Everett J
(2020)
Iron stored in ferritin is chemically reduced in the presence of aggregating Aß(1-42).
in Scientific reports
Everett, J.
(2018)
Nanoscale Examination of Biological Tissues Using X-ray Spectromicroscopy
Finnegan ME
(2019)
Synchrotron XRF imaging of Alzheimer's disease basal ganglia reveals linear dependence of high-field magnetic resonance microscopy on tissue iron concentration.
in Journal of neuroscience methods
Goenaga-Infante, H.
(2019)
Glossary of Methods and Terms used in Analytical Spectroscopy
in Pure and Applied Chemistry
Hitchcock AP
(2018)
Correlative Spectromicroscopy and Tomography for Biomedical Applications involving Electron, Ion, and Soft X-ray Microscopies
in Microscopy Today
Lermyte F
(2019)
Top or Middle? Up or Down? Toward a Standard Lexicon for Protein Top-Down and Allied Mass Spectrometry Approaches.
in Journal of the American Society for Mass Spectrometry
Lermyte F
(2020)
Metallic iron in cornflakes.
in Food & function
Lermyte F
(2019)
Metal Ion Binding to the Amyloid ß Monomer Studied by Native Top-Down FTICR Mass Spectrometry.
in Journal of the American Society for Mass Spectrometry
| Description | The methodologies we have developed in this project represent a significant advance in the application of synchrotron x-ray approaches to analyze human tissues. In particular, we have used the exceptional chemical and magnetic sensitivity of x-ray techniques to map the biochemistry of brain tissue on sub-cellular length scales, enabling the detection of nanoscale deposits of copper and iron in differing forms. These nanoscale deposits were found within amyloid plaques, a hallmark pathological lesion of Alzheimer's disease. We relate them to links between disrupted metal homeostasis, the development of Alzheimer's disease, and the formation of pathological amyloid lesions. Concurrently, we developed new methods that use x-ray chemical spectroscopic signatures to map the spatial distribution of important biological compounds of relevance to neurodegenerative diseases. In addition to studying ex vivo tissue, we also performed experiments on in vitro samples, and established a link between amyloid aggregation and the chemical reduction of iron biominerals within the iron storage protein ferritin. Together, these experiments reveal a new level of complexity in the role of metals in neurodegenerative diseases and add new concepts to our current understanding of human neurobiology. Further to this, the project unveiled an unexplored fundamental step in the development of Alzheimer's and related diseases, and opened up new research avenues for the study of disease aetiology, treatment, and diagnosis. In addition, our findings raise questions about the (patho)physiological impact of amyloid in association with iron and other metals, especially given the properties of the iron, copper, and calcium forms detected in association with the amyloid plaques. |
| Exploitation Route | Through this project, we were able to engage with the global academic and clinical research communities, and successfully demonstrated how specialist techniques such as x-ray spectromicroscopy and FTICR mass spectrometry can be applied to new research areas crossing biochemistry and medical themes. The results of the project have opened up new research avenues for the study of the aetiology, treatment, and diagnosis of neurodegenerative and other diseases where nanoscale biochemistry plays a significant role. We are already observing evidence of the impact of our work with our project publications receiving rapid and diverse recognition across the global academic and medical community. Further collaborative projects that build on our successes here are currently in development, including a collaborative project funded by the Kleberg Foundation (PI Prof George Perry, UTSA, USA) that challenges long-held assumptions about the toxicity of amyloid in the human brain. |
| Sectors | Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| URL | https://www.chemistryworld.com/news/biochemical-mystery-unfolds-as-elemental-metals-found-in-alzheimers-patients-brains/4013853.article |
| Description | The impact of this work is recorded against grant ref EP/N033140/1. Additionally, we are receiving 6-monthly impact reports for the Futurum article that was generated as one of the outputs from this project as a public engagement/education resource: https://futurumcareers.com/shining-a-light-on-the-role-of-trace-metals-in-neurodegenerative-diseases The April 2023 impact report is not yet available at the time of writing (March 2023), but the previous October 2022 impact report showcased the reach and use of the article as follows. Full details are available on request. Our article was published in Futurum on 14th May 2022, and over the next 6 months our resource reaching over 32k people via social media (Twitter, Facebook, Pinterest, Instagram) and via the dedicated article website. This has led to hundreds of 'likes' and downloads, with some continuing to download the activity sheets as well as the article, and the materials are also being downloaded from other sites as a free international resource for teachers (e.g. www.tes.com/teaching-resource/resource-12678046, https://www.teacherspayteachers.com/Product/The-role-of-trace-metals-in-neurodegenerative-diseases-8073701?st=f17c0f85, and https://www.scientix.eu/resources/details?resourceId=29799). The resource highlights the use of advanced analytical science methods in the study of brain disorders, and also highlights the role of major science facilities - in this case, Diamond Light Source synchrotron in the UK. |
| First Year Of Impact | 2022 |
| Sector | Education |
| Impact Types | Societal |
| Description | Input into Diamond II Science Case |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Contribution to a national consultation/review |
| Description | Roundtable on air pollution and dementia hosted by the Alzheimer's Society |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| URL | https://www.alzheimers.org.uk/for-researchers/report-on-link-between-air-pollution-and-dementia |
| Description | Amyloidß Protective Hypothesis: A Cure for Alzheimer's Disease |
| Amount | $1,200,000 (USD) |
| Organisation | Robert J Kleberg Jr and Helen C Kleberg Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 01/2021 |
| End | 12/2024 |
| 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 | UKRI COVID-19 Grant Extension Allocation |
| Amount | £104,408 (GBP) |
| Organisation | United Kingdom Research and Innovation |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2021 |
| End | 09/2021 |
| Description | Warwick-Wellcome Translational Partnership Award: Fellowship |
| Amount | £93,000 (GBP) |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 02/2023 |
| End | 12/2023 |
| Title | Neuromelanin imaging |
| Description | Identification and use of feature in soft x-ray spectrum to image neuromelanin, demonstrated in human brain tissue where the neuromelanin was identified independently of the surrounding tissue. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2020 |
| Provided To Others? | Yes |
| Impact | 1. Supported progression of researcher into funded postdoctoral position. 2. Work featured in forthcoming DLS Annual Report to showcase work at the beamline where the method was developed. |
| URL | https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202000239 |
| Title | XMCD technique developed at Diamond beamline I08 |
| Description | We successfully demonstrated the x-ray magnetic circular diochroism method for use in spectromicroscopy, for the first time at beamline I08 at Diamond Light Source. This method enables the magnetic character of nanoscale regions to be assessed within sample. Using this method we were able to determine the magnetic state of some iron biomineral inclusions in Alzheimer's plaque material extracted from human brain tissue. We have added this new data to paper currently under revision for the journal Nanoscale. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | Broader impacts will be generated in the longer term. |
| Description | AlzForum debate |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Contributed invited response to an article on the USA AlzForum site: "Does High Iron Push a Person With Pathology Into Dementia?" |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.alzforum.org/news/research-news/does-high-iron-push-person-pathology-dementia |
| Description | Frederik Leremyte presentation at 66th Conference on Mass Spectrometry and Allied Topics |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Presentation delivered at the 66th ASMS Conference on Mass Spectrometry and Allied Topics. The conference remains at the forefront of mass spectrometry and attracts a wide range of delegates from academic and R&D areas. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://www.asms.org/conferences/annual-conference/annual-conference-homepage |
| Description | Invited seminar at Loughborough University |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | Seminar describing activity of my research group in the area of biomedical nanomagnetism. A substantial part of the talk was dedicated to reporting results from our recent EPSRC projects. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.lboro.ac.uk/departments/physics/events/seminars/landau-seminars/landauseminars2021/landa... |
| Description | Jake Brooks - Oral presentation at Early Career Research in Biological Physics event, run by IOP Biological Physics group |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | The aim of the meeting was for early career researchers (both members and non-members of the biological physics group) to showcase a range of experimental and theoretical research within the biological physics remit. The meeting also provided an opportunity to discuss the challenges faced by early career researchers during the pandemic. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.iopconferences.org/iop/frontend/reg/thome.csp?pageID=1095187&eventID=1777&traceRedir=2 |
| Description | Jake Brooks - Oral presentation at MMC conference 2021 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | The aim of the conference is to showcase developments over a breadth of topics within the fields of microscopy, cytometry and imaging. I presented our work on synchrotron analysis of Parkinson's disease tissue, which sparked a follow-up discussion with a member of staff at ESRF's ID16a beamline concerning potential future usage of ID16a by our group. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.mmc-series.org.uk/mmc2021/ |
| Description | Jake Brooks - Poster presentation at ADPD 2021 conference |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | The aim of the conference is to unite a wealth of international expertise on Alzheimer's disease, Parkinson's disease and related neurodegenerative disorders to present findings and discuss on the most recent developments in the understanding, diagnosis and treatment of these disorders. I presented our published works on using synchrotron x-ray spectromicroscopy to for in situ characterisation of neuromelanin and its associated metal ions. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://adpd2021.kenes.com |
| Description | Jake Brooks poster presentation at the International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (ADPD) 2022 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Presenting research findings to the clinical and basic research communities engaged with Alzheimer's and Parkinson's disease research |
| Year(s) Of Engagement Activity | 2022 |
| Description | James Everett invited talk at Diamond-II Workshop: Imaging |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | The aims of the workshop were to introduce Diamond-II, to discuss its potential benefits for the existing facilities, and to develop the science case for the machine upgrade. James's talk presented our work on x-ray spectromicroscopy and discussed how Diamon-II would impact on this. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://www.diamond.ac.uk/Home/Events/2018/DiamondIIBioIma.html |
| Description | James Everett oral presentation at the International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (ADPD) 2022 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Dissemination of research outputs from EPSRC project. |
| Year(s) Of Engagement Activity | 2022 |
| Description | James Everett poster presentation and talk at Microscience Microscopy Congress 2021 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | Dissemination of research outputs from EPSRC project. |
| Year(s) Of Engagement Activity | 2021 |
| Description | James Everett poster presentations at the International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (ADPD) 2021 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Dissemination of research outputs from EPSRC project as x 2 posters.. |
| Year(s) Of Engagement Activity | 2021 |
| Description | James Everett presentation at UKSR50 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | A conference to celebrate the achievements and explore the future of the light sources (Synchrotrons and FELs) and their applications in the coming decades. |
| Year(s) Of Engagement Activity | 2018 |
| URL | http://www.uksr50.org/ |
| Description | James Everett talk at XRM2018 conference |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Oral presentation by team member at the International Conference on X-ray Microscopy (XRM2018). XRM2018 brought together experts in the development and use of X-ray microscopes. This conference addressed the most recent advances in X-ray microscopy technology and applications through a program of talks, posters, and social interaction. |
| Year(s) Of Engagement Activity | 2018 |
| URL | http://xrm2018.com/ |
| Description | Jierong Luo talk in Barcelona at the International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (ADPD) 2022 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | To communicate findings from the EPSRC research project, concerning the impact of iron and amyloid on MRI signal, with the wider clinical and basic research communities engaged with Alzheimer's and Parkinson's research. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Lorentz Center workshop: Iron in the Fire |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Collaborative bid to host workshop at the Lorentz Center, Leiden, on 'Iron in the fire', bringing together a panel of international speakers, spanning early career to senior leaders in the field, for a 5-day workshop in March 2022 (hybrid format: online and in-person) |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://www.lorentzcenter.nl/iron-in-the-fire-2022.html |
| Description | Publication with Futurum on our team and synchrotron research, providing an open-access educational resource for schools |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Schools |
| Results and Impact | Developed a publication with Futurum which will be promoted and provided open-access to schools - a profile of team members to explain how they came into a research career and their experiences, and an introduction to research at synchrotron facilities, and the specialist field of the team. |
| Year(s) Of Engagement Activity | 2022 |
| Description | STEM for Britain |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Policymakers/politicians |
| Results and Impact | Selected presentation by JB of selected work arising from this project at the 2020 STEM for Britain event, showcasing the work to Members of Parliament. |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://stemforbritain.org.uk/ |