A molecular David slaying Goliath

The Cavendish Building of Homerton College Cambridge, May 2011At the start of this week I was at an excellent conference hosted in Cambridge’s Homerton College – the building where we had our meals is shown on the left. It was thoroughly enjoyable, and I learnt a lot. There were some superb talks. I thought the best was one by Prof David Klenerman. It was on the molecular and cell behaviour that underlies Alzheimer’s disease.

Understanding this disease is a very hard problem but David Klenerman and his coworkers are making progress at understanding what is going on. Their work starts by studying what is believed to be the culprit: a fragment of a protein called amyloid-β. This fragment is found in fibre-like aggregates of many millions of these molecules, and these fibres are visible in the brains of those who have died with Alzheimer’s. But there is evidence that it is not these easily observable fibres but much much smaller clusters of maybe 10 or fewer fragments, that cause the nerve cells to die and so people to suffer Alzheimer’s. Klenerman and coworkers show evidence that it may be that a single cluster (possibly a cluster that is unusual in some way) can damage a cell significantly.

This is quite remarkable. A cell would have a volume perhaps 100 billions times* that of a cluster – this is a very small David slaying a much much larger Goliath.

So how do you detect this tiny David? Klenerman and coworkers use a clever method. In solution, only a few % of the amyloid-β fragments are in clusters, most are on their on their own. So the first task is to distinguish between these clusters and the much more numerous fragments that are on their own.

They attach a red tag to some of the fragments and a green tag to others, and then focus a laser down to a tiny spot, only about the wavelength of light across. Fragments wander into and out of this spot. If it is a fragment on its own, then if it is green then they see green light while if it is red they see red light.

But if it is a cluster it may contain fragments with green and red tags, so they will simultaneously see red and green light – and that can only be from a cluster. This enables them to distinguish between the tiny clusters and the much more numerous fragments that are on their own.

Having found these tiny clusters they went on to show that even tiny amounts of them can harm a cell. Concentrations of less than one part in a billion can harm a type of brain cell called an astrocyte, possibly by punching tiny holes in the outer membranes of the cells.

We still have a long way to go before we translate this understanding of what the fragments are up, into treatments. But even here there are hints. Klenerman and coworkers showed that another protein, called clusterin, can protect cells, so perhaps if we can figure out how to make our brains make more of this protein we could stop, or at least greatly slow down, this disease.

*100 nm3 versus 1013 nm3.

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