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Details of Grant 

EPSRC Reference: EP/X031403/1
Title: Probing the origin and evolution of low-oxidation state iron and copper nanoparticles in the brain
Principal Investigator: Telling, Professor ND
Other Investigators:
Gates, Dr M Harrison, Professor R
Researcher Co-Investigators:
Dr J Everett
Project Partners:
Diamond Light Source Newcastle University University of Texas at San Antonio
Department: Inst for Science and Tech in Medicine
Organisation: Keele University
Scheme: Standard Research
Starts: 01 May 2024 Ends: 30 April 2027 Value (£): 857,013
EPSRC Research Topic Classifications:
Analytical Science Biomedical neuroscience
Environment & Health Medical science & disease
EPSRC Industrial Sector Classifications:
No relevance to Underpinning Sectors
Related Grants:
Panel History:
Panel DatePanel NameOutcome
25 Oct 2023 EPSRC Physical Sciences Prioritisation Panel A October 2023 Announced
Summary on Grant Application Form
Neurodegenerative diseases such as Alzheimer's and Parkinson's are characterised by abnormal levels of naturally occurring proteins that clump together to form dense deposits in the brain. In Alzheimer's these deposits are formed from the amyloid-beta protein, and often termed amyloid plaques. The ways in which these plaques influence the onset and progression of the disease are still not fully understood. However, detailed studies of amyloid plaques have revealed a prevalence for them to contain microscopic particles (called nanoparticles) of different metals.

It is not surprising to find metals in the brain, as the human body needs an incredible range of at least 10 different metallic elements in its everyday function, with much of our iron present as tiny nanoparticles of iron oxide (a form of rust). What is far more surprising is that the iron and copper nanoparticles we have observed within amyloid plaques, are not typical of oxidized metals such as rust. Instead, using sophisticated x-ray microscopy methods, we found that these particles were in fact stabilized in what are called low-oxidation states, including pure metallic elemental forms.

This discovery is akin to finding a shiny metallic iron nail after it has been left in a field for many years. Just as we would expect the nail to oxidize over time due to the chemical reactivity of the metal surface, the nanoparticles (which have a much higher surface area relative to their size) are even more likely to oxidize. This surface reactivity can also result in toxicity when such nanoparticles are exposed to living tissue. Therefore, understanding how nanoparticles in this low-oxidation state are stabilized within the protein deposits found in the brain, could provide crucial insight into the interplay between metals and proteins in the brain and how this contributes to aging and disease.

It is possible that the metal oxide nanoparticles themselves could drive the abnormal protein deposition, and in the process be transformed to low-oxidation states. Looking for evidence that these metal-protein interactions occur in brain tissue, as well as investigating the mechanisms by which the transformations could proceed, is one of the key aims of this project. Equally important though is finding the source of the oxidised metal particles that are transformed by the proteins. Interactions could occur between proteins and biological sources of metal oxides already present in the brain, but it is also possible that sources from outside the body are involved.

Substantial evidence now exists suggesting ultrafine metal oxide particles that are present in some airborne forms of pollution, can enter the brain. It seems they do this via routes that bypass the brain's natural defences that normally prevent foreign material entering. A further aim of this project is therefore to investigate environmental nanoparticles collected from sites of known pollution in the UK, and to assess the likelihood that such particles are transformed to low-oxidation states in the brain.

The project will use new state-of-the-art methods combined with physical science approaches, to build fundamental new knowledge regarding the biochemical processes that connect metals and proteins with aging and disease in the human brain. This will be of particular importance in the development of new drugs to treat diseases such as Alzheimer's, which currently focus only on the protein deposits with modest levels of success. Combined strategies that also target metals will offer new hope for effective treatments, whilst knowledge of how iron oxides are transformed could help develop more sensitive MRI diagnosis. The latter could use the accumulation of metallic forms of iron during protein aggregation to detect key changes in the brain prior to brain atrophy. Ultimately this could have huge impact on early interventions, with treatments tailored to target specific metal forms.

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Organisation Website: http://www.keele.ac.uk