Tracking the movements of the killer behind dementia and heart disease

A clogged artery- arteriosclerosis

A clogged artery. Credit: dreamstime
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Cholesterol is vital to the human body. It is an essential component in the membranes of cells as well as necessary for the production of important hormones and the transport of chemical signals. But we know cholesterol can also be damaging – it has been linked to heart disease, strokes and more recently Alzheimer’s disease.

According to the British Heart Foundation, 6 in 10 adults in England have high blood cholesterol levels, causing some of the cardiovascular diseases which are the UK’s biggest killer. Recent studies have also shown that there are direct links between high levels of cholesterol in the blood and amyloid plaques in the brain, which are the cause of Alzheimer’s.

All these diseases are related to the way the transport of cholesterol in and between cells is being hijacked in some way. So it is necessary to fully understand the processes of cholesterol transport.

However, research data into cholesterol transport between and within lipid membranes has proved to be inconsistent and unreliable. For example, studies have shown that the time scale for cholesterol to "flip" in a membrane's lipid bilayer varies from several hours to a few milliseconds. Dr Lionel Porcar and his colleagues at Institute Laue Langevin in Grenoble and Professor Ursula Perez-Salas from the University of Illinois have found that one reason these differences exist is related to the fluorescent chemical tags and other substances used to track cholesterol in many of these other studies.
The team used small angle neutron scattering to follow cholesterol movement. Using neutrons produces very reliable results because the chemical identity of the molecule under investigation remains unaltered. The researchers began with a mix of cholesterol-enriched and cholesterol-free bubbles of artificial lipid membrane, known as vesicles, dispersed in water and then zapped them with a beam of neutrons. Using deuterated lipids, the researchers were able to adjust conditions so that only neutron scattering by cholesterol was visible. The results showed that the movement of cholesterol both within the membrane, also referred to as flipping, and from one vesicle to another was slower than measured in most previous studies — it took on the order of a few hours.

"This study was the first complete accurate measurement of pure cholesterol transport," says team member Lionel Porcar at the Laue-Langevin Institute. "Most of the other studies tell us about fluorescent cholesterol, which is not what we have in our bodies."

This result is not enough to settle the debate, however. The very slow flip rate was particularly surprising and would certainly be significant if there are other ways to show confidence in the result. Therefore the team is now pursuing the study of cholesterol flipping in single membranes using neutron reflectivity on INTER at ISIS where it is possible to track fast cholesterol movement between the membrane's leaflets. However the research process has not been straightforward - early versions of the membranes had holes, which gave an inaccurate picture of how cholesterol moved and it has taken the team several attempts to get these membranes up to scratch. Now that the team has workable membranes they plan to carry out experiments using even more complicated membrane models which will more closely resemble those found in cells.

The research is fundamental, but understanding how cholesterol moves through the human body may improve models of how diseases like Alzheimer's develop. Porcar and his colleagues believe that understanding the movement of cholesterol in and out of cells is an important step in mapping its relationship to Alzheimer's and other illnesses. "Once we understand the mechanism, that will have a lot of potential application for diseases," he says.

Ursula Perez-Salas and Amy Redhead

Research date: July 2014

Further Information

Reference:

Reed, B., Villeneuve, S., Mack, W., DeCarli, C., Chui, H. and Jagust, W. (2014). Associations Between Serum Cholesterol Levels and Cerebral Amyloidosis. JAMA Neurol, 71(2), p.195.

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