(The Bank Statement is also available as a PDF document.)

The 6 projects described below were made possible only by the generosity and forethought of the people who have donated their tissues to research on MS.

Is working harder bad for the axon?
Dr Philip Nichols
MS Research Group, University of Newcastle upon Tyne

An examination of MS lesions reveals two casualties myelin and axons. What is less clear is how these injuries occur. Over the last two years, Dr Nichols group has been trying to find out how axons are damaged in MS lesions; and what role special structures within the nerve cell - the mitochondria play in this damage.

The mitochondria, one shown here in a cartoon, provide energy to the cell and so are referred to as the cell's batteries In nerve cells, mitochondria provide the energy that is needed to drive nerve impulses along the axon. The group asked do the batteries in axons within lesions have to work harder? In order to answer this they examined brain tissue from MS donors that contained a lesion and an adjacent sample that appeared normal They first confirmed the presence of a lesion by treating a very thin slice of the tissue with a dye that stains myelin blue. They then cut another slice and used a special dye with which they could see how hard the mitochondria were working.
The picture in the top left panel (below) shows normal tissue with normal amounts of myelin (dark blue); a lesion in which the myelin has been destroyed is shown top right (lack of blue). The brown stain in the bottom panels shows the activity of mitochondria the darker staining of the tissue containing the lesion (bottom right) demonstrates that the mitochondria were more active in the lesion.

This is perfectly understandable, as an axon devoid of the insulating layer of myelin will need more energy to conduct nerve impulses than a fully insulated, myelinated axon. But, is it possible that the very system by which the axon is trying to cope with the lack of myelin is actually making it more vulnerable to damage and eventual death? In order to answer this, Dr Nichols group is now trying to find out whether an unfortunate side effect of the increased activity of the mitochondria could contribute to axons being damaged within lesions. Understanding the exact mechanism of this could provide a target for treatments aimed at stopping damage to axons and this would in turn bring us one step closer to limiting or even preventing the disability caused by MS.

Chemicals that draw big eaters to a site of injury
Professor Yoh Matsumoto
Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan

Professor Matsumoto's group is following another lead to explain the injury to axons. The amount of axonal damage within a lesion has been linked to the number of a particular type of cell called a macrophage present at the crime scene Macrophages release toxic chemicals that kill bacteria and tumour cells, and they then engulf and digest the resulting debris. Since these activities could be directed to injuring axons, it is vital to control this powerful cell within the brain. Professor Matsumoto has gone to the very beginning of the chain of events and asked: What initially draws macrophages to a site where axons are or about to be injured?

Chemicals that cause cells to move towards the site of release are called chemokines, and the group found two types in MS lesions: monocyte chemoattractant-1 (MCP-1) and interferon-gamma inducible protein-10 (IP-10). It is known that MS lesions grow by expanding outward from a central starting point. This means that in a large active lesion, the ongoing destruction will be occurring on the lesion edge. High concentrations of MCP-1 and IP-10 were found on the rim of the lesions, and low levels in the inactive, lesion centre and in the surrounding normal tissue.

These pictures from Professor Matsumoto's research show on the left a thin slice of tissue treated with the blue myelin dye demonstrating the presence of a large lesion. The next slice was treated with a stain that picks up the chemokine MCP-1. The three high power views on the right, show low amounts of MCP-10 at the centre and outside the lesion and large amounts on the lesion rim (small brown dots). Similar pictures were seen when slices were stained for IP-10.

Large numbers of macrophages were also found in the rim, and these had on their surface receptors that would capture MCP-10 and IP-10.  Importantly these macrophages had produced a toxic enzyme (matrix metalloproteinase) that is capable of damaging axons. 
So it seems that as lesions expand, more and more macrophages are drawn to the active edge by MCP-1 and IP-10; once there, the cells attack the axon, and perhaps the myelin and then engulf and digest fragments of the resulting debris.  The important role played by chemokines in guiding macrophages to the edge of a lesion, provides a target for therapies, since stopping the action of chemokines would stop macrophages from reaching the crime scene and injuring

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