Dr Joanna Collingwood

Examining the role of anomalous iron concentrations in Alzheimer's disease, and their implications for early detection and diagnosis

Fellowship grant
Keele University
Supervised by: Dr John Dobson
Grant amount: £120,283
Start date: 1 January, 2003
Completion date: 30 June, 2006

What is already known about the proposed research topic?

Recent research has linked unusually high levels of iron in brain tissue to Alzheimer's disease (AD), and other neurodegenerative diseases.

• Iron is essential to many of the body's processes, so the body stores it in order to maintain a regular supply. However, in certain forms iron can be toxic to cells. (Iron is usually combined with other elements, particularly oxygen, in the human body. This produces various iron compounds with different properties.) The body absorbs iron from food and stores it as 'ferritin': spherical protein shells that can hold up to 4500 iron atoms. Iron stored in ferritin is not magnetic.
• It has been shown that there are higher levels of iron in Alzheimer's disease brain tissue, but the amount of ferritin does not appear to increase.
  This suggests that the extra iron atoms are not being stored in the normal way. Studies have suggested that the ferritin protein may be getting overloaded with iron atoms, and that some iron is being stored in a form known as magnetite. Magnetite is magnetic at body temperature, and was first discovered in tiny quantities in human brain tissue in 1992.
• Experimental evidence suggests that magnetite is present in diseased brain tissue. Also, specific ways in which magnetite could influence the onset and progression of neurodegenerative disease have been proposed.
• However, the relationship between the higher concentrations of iron associated with Alzheimer's disease, and their implications for the disease, is poorly understood. It has not been possible to establish in detail the form of the additional iron, its location relative to diseased structures in brain tissue, and the precise way in which magnetic particles like magnetite could influence cell behaviour. This is largely because until now, there has been no reliable and efficient means of mapping and characterising tiny iron deposits in tissue samples.

What do you hope to find out?

• If there is an association between the location of the additional iron seen in Alzheimer's disease tissue, and the diseased tissue areas and plaques in the brain on a microscopic scale.
• If the additional iron present in AD tissue is in a magnetic form.
• To examine how magnetic iron particles could influence the formation of plaques like those found in AD tissue.

What methods will you use to investigate the research topic?

Mapping the iron in brain tissue with high-energy x-rays:

• Until now, tissue-staining techniques have been used to locate iron in human tissue under a normal microscope. This is time-consuming, not very precise, and does not show what type of iron is present. Therefore, a new technique is being developed that should make it possible to map and characterise tiny concentrations of iron in brain tissue. High-energy x-rays are used to scan an area of tissue on a very fine scale (the resolution is smaller than a single cell). Both the precise location of the iron deposits, and their form (e.g. ferritin, magnetite, haemoglobin), can be found this way, and now that a successful pilot study has been done using avian (pigeon) tissue, it should be possible to extend the method to human tissue. Example x-ray data, based on scans from the pilot study on avian tissue, is shown in Fig 1.

Looking at the relationship between iron deposits and structures in the tissue:

• A variety of suitable imaging and magnetic property analysis techniques, available at the host institution and through collaboration, will be used to look directly at the relationship between cells and structures in the brain tissue, and the iron concentrations located using x-rays.
  

Figure 1: Three x-ray scans are shown above. The top scans are made at a chosen energy that excites iron to produce a strong signal. The three sharp peaks seen in the scanned areas confirm that there are three iron anomalies in the tissue samples. The anomalies are mapped to the lower x-ray transmission image of the tissue, and are identified here with black markers. The zinc wires shown are deposited onto the substrate to provide a grid system for mapping. The anomalies are then scanned individually and it is shown that one is due to ferritin and two are due to magnetite.

Investigating the effect of magnetic iron particles on plaque formation:

• A controlled series of laboratory tests will examine the effects of synthesised magnetite particles (typical in size of those found in the human brain), on the biochemical processes involved in plaque formation. A preliminary investigation by the group has already shown that a certain form of plaque deposition is increased in the presence of synthesised magnetite particles.

How will your findings be put into practice, and how will the research improve the lives of people with dementia and/or their carers?

• The mapping and characterisation techniques should, in combination, provide a detailed picture of the distribution and form of iron in brain tissue. This should show if, as suggested by many studies, there is a link between elevated iron concentrations in the brain, their magnetic state, and neurodegenerative disease. This will improve our understanding of the role of iron in Alzheimer's disease, and may lead to effective methods of diagnosis and treatment based on these results.

• The investigation of the effects of magnetite on plaque formation will help us to understand if and how magnetic iron concentrations in the brain could affect the onset and progression of Alzheimer's disease.
  
• Detecting and diagnosing Alzheimer's disease is currently extremely difficult. However, if there are elevated levels of magnetic material associated with the disease, then it should be possible to develop scanning techniques (based on existing Magnetic Resonance Imaging [MRI] methods), that could provide a means of early detection and diagnosis.