In the pursuit of dangerous clumps

Related images
(click to enlarge)

Adrian Keller

When normal proteins form protein clumps in the body, then alarm bells start ringing. Such clumps, called "amyloids," are closely associated with Alzheimer's disease and type 2 diabetes, formerly called adult-onset diabetes. If doctors knew how these proteins form clumps, then they might be able to treat such diseases more efficiently. The physicist Adrian Keller and his colleagues at the Helmholtz-Zentrum Dresden-Rossendorf and the university in Aarhus, Denmark, have succeeded in taking a major step in that direction. The cell surface assumes a major role in this because the proteins are deposited there and form clumps. In type 2 diabetes and Alzheimer's, amyloids form on specific cells of the pancreas and the brain, respectively. Even with modern high-performance instruments, it is not possible to observe these processes within the body. Scientists like Adrian Keller, who currently pursues his research at the Interdisciplinary Nanoscience Center "iNano" in Aarhus, are actually attempting to recreate these processes with real proteins on artificial surfaces in the lab.

This sounds easier than it really is. It seems that the formation of these clumps is influenced primarily by the surface's hydrophilicity and hydrophobicity. Hydrophilic surfaces are easy to wet whereas hydrophobic ones tend to repel water.

Adrian Keller has succeeded in customizing the surface of mica with an apparatus at the Helmholtz-Zentrum Dresden-Rossendorf. Slow, positively charged atoms of the rare gas argon penetrate only slightly into the crystal surface at low velocity. "This chemically activates the surface without significantly changing the roughness," explains Adrian Keller the first step of the customization process. Changing the roughness would also have considerable influence on the formation of amyloids.

In the second step, the mica with the activated surface are simply stored in boxes in the lab for several weeks. During this time, the crystal slowly adsorbs hydrocarbons from the air. These turn the initially hydrophilic surface over time into a more hydrophobic surface until after about three months it is completely "water repellent."

During these three months, Adrian Keller can conduct his experiments and always knows exactly how hydrophobic the mica is at any given moment. He deposits a small protein called "amylin" on the crystal. Specific cells of the pancreas produce this substance together with insulin. If type 2 diabetes develops, the organism initially reacts less well to insulin which regulates the blood sugar level. The pancreas, in turn, produces more insulin and also more amylin. This increases the amylin concentration, and a few amylin proteins suddenly assume a different shape. This process resembles a bit an umbrella turned inside out by a strong gust of wind; thus, creating a sort of "rain bowl."

The first proteins changed in this manner also influence neighboring proteins and transform additional amylins. The proteins which were turned inside out, in turn, begin to aggregate and amyloids are created. These destroy the surface of some cells and, thus, lower the production of insulin. The organism, in turn, increases the activities of the remaining cells and starts a dangerous cycle which, in the end, can paralyze the entire insulin production.

When the surface in Adrian Keller's experiments is hydrophilic, then amylin aggregates on the mica into protein clusters which are called "fibrils." If, however, the surface has aged a few weeks and, thus, becomes more hydrophobic, then tiny clumps are formed which are called "oligomers." Fibrils and oligomers destroy the cell surface through different mechanisms and, thus, prevent the production of insulin. With the customized surfaces created by the Helmholtz researchers in Dresden, it is now possible for the first time to observe the clumping process of the proteins in detail. One day, strategies might get discovered to prevent the aggregation and, thus, also the development of the disease. And not just for type 2 diabetes, but maybe also for the currently incurable Alzheimer's disease.

Source: Helmholtz Association of German Research Centres