Short segments of sugar chains useful in search for new drugs for Alzheimer's

Heparansulfate, which is needed for normal fetal development among other things, is also important for the build-up of amyloid, morbid protein deposits that appear in several serious diseases. This is shown by Uppsala scientists in an article published in the Proceedings of the National Academy of Science.

Heparansulfate, long chains of sugar molecules, is produced by most cells in the body. It was not previously known that heparansulfate is necessary for the occurrence of amyloid, abnormal protein deposits in the body. Amyloid appears in several grave disorders, such as Alzheimer's disease, mad-cow disease, old-age diabetes, and so-called AA amyloidosis, which often develops in chronic inflammatory diseases.

The research team is headed by Professor Ulf Lindahl and Associate Professor Jin-ping Li at the Department of Medical Biochemistry and Microbiology at Uppsala University. They have studied how heparansulfate binds the abnormal protein molecules and thereby triggers amyloid deposits. In experiments the researchers have used genetically altered mice that produce much higher than normal amounts of the enzyme heparanase. This enzyme cuts the normal-length heparansulfate chain into short segments. Both the genetically altered and the normal control mice were stimulated with a treatment that usually leads to rapid build-up of amyloid (AA amyloidosis) in several internal organs, including the liver, the kidneys, and the spleen. The heparanase-producing mice proved to be completely resistant to amyloidosis of the liver and kidneys, organs with pronounced overproduction of the enzyme and therefore very short heparansulfate fragments. On the other hand, they did develop amyloid in the spleen, which had avoided overproduction of heparanase and therefore contained normal size heparansulfate. The control mice developed amyloidosis of the spleen and of the liver and kidneys. The findings indicate that the occurrence of normal size heparansulfate is a precondition for the development of AA amyloidosis. Since accumulations of heparansulfate also occur in other types of amyloid deposits, the researchers conclude that the connection is generally valid.

"The findings provide hope that short segments of sugar chains will be useful in drugs for Alzheimer's and other amyloid disorders in the future. But first such compounds need to be carefully tested in test tubes and then assessed in comprehensive animal experiments. Only then will it be possible to introduce testing in patients," says Professor Ulf Lindahl.