X-ray research advances understanding of Alzheimer’s disease

Research to be published in this week’s issue of the journal Nanoscale is helping to increase understanding of the impact of metals in the brain which may drive the progression of Alzheimer’s disease, and how the management of these metals could lead to more effective treatments for Alzheimer’s in the future.

There are 850,000 people with dementia in the UK, with numbers set to increase to over one million by 2025, rising to two million by 2051. There is currently no cure for Alzheimer's disease or any other type of dementia. Delaying the onset of dementia by five years would halve the number of deaths from the condition, saving 30,000 lives a year.

The ‘breakthrough’ research, funded by the Engineering and Physical Sciences Research Council (EPSRC), identified certain properties of the metals found in brains affected by Alzheimer’s, including a chemically reduced iron species, with mineral forms including a magnetic iron oxide, which the research team hypothesize is associated with the formation of amyloid protein plaques in the brain. The formation of these amyloid plaques - which are abnormal clusters of proteins in the brain - is associated with toxicity which causes cell and tissue death, leading to mental deterioration in Alzheimer’s patients.

The international research collaboration led by Professor Neil Telling at Keele University and Dr Joanna Collingwood at the University of Warwick also involves the University of Florida, The University of Texas at San Antonio, along with the Advanced Light Source in Berkeley, USA and the Diamond Light Source synchrotron in Oxfordshire.

Professor Neil Telling, Professor of Biomedical NanoPhysics at Keele University, comments:

“Although iron mineral deposits have been associated with Alzheimer’s before, this study goes much further by using advanced x-ray microscopy techniques to probe the chemical state, magnetic properties, and the size and shape of the iron deposits, without removing them from the amyloid plaques. The iron deposits we observed are unusual as they are unstable and so would normally react rapidly with oxygen in the air to form more stable minerals. The presence of such reactive forms of iron in amyloid plaques is particularly interesting as they could contribute to the toxicity that drives Alzheimer’s disease progression, via the production of harmful free radicals.”

The research team found that in brains affected by Alzheimer’s, several chemically-reduced iron species, including a proliferation of a magnetic iron oxide called magnetite - which is not commonly found in the human brain – occur in the amyloid protein plaques. Further, they found that the chemical form and shape of the mineral deposits were quite different to those reported by others, where environmental pollution was suggested as a possible origin of the material.

Previous research by the team has shown that similar materials can be found in the brains of mice that contain amyloid plaques, and also that these minerals can form when iron and the amyloid protein interact with each other under laboratory conditions.

Thanks to advanced measurement capabilities at synchrotron X-ray facilities in the UK and USA, including the Diamond Light Source I08 beamline in Oxfordshire, the research team now has detailed evidence that these processes took place in the brains of individuals who had Alzheimer’s disease. They also made unique observations about the forms of calcium minerals present in the amyloid plaques.

Understanding the significance of these metals to the progression of Alzheimer’s could lead to more effective future therapies which combat the disease at its root.

Professor Telling continues:

“We were able to make this discovery by extracting amyloid plaque cores from the donated brain tissue of two deceased patients who had Alzheimer’s disease. The fact that these new observations are so similar to our previous findings in mice and in artificial materials prepared in the laboratory, is particularly exciting as it suggests a common mechanism may be at play. This work is part of an ongoing programme that also showcases how advanced x-ray techniques that are used in the physical sciences, can also be applied to good use in the study of disease. As well as improving our understanding of this terrible progressive disease, the findings impact on clinical trials for future treatments, such as those using iron modifying drugs at the Florey Institute of Neuroscience and Mental Health in Australia.”

The researchers scanned the plaque cores using state-of-the-art X-ray microscopy at the Advanced Light Source in Berkeley, USA and at beamline I08 at the Diamond Light Source synchrotron in Oxfordshire, to determine the chemical properties of the minerals within them.

They also analysed the magnetic state of the iron species in the plaques to confirm the presence of various iron minerals including the magnetic iron oxide magnetite.

The research team propose that interactions between iron and amyloid that produce the chemically reduced iron species, including magnetite, may account for toxicity that contributes to the development and progression of Alzheimer’s.