BioWorld International Correspondent

LONDON - An international team of researchers has solved one of the biggest puzzles facing those working on Alzheimer's disease. For more than 20 years, scientists have known that amyloid precursor protein (APP) accumulates in the brain in those with Alzheimer's disease - but no one has been able to work out the normal function of the protein.

The work of Tobias Hartmann and colleagues at the Centre for Molecular Biology Heidelberg in Germany, together with collaborators in Belgium and the U.S., now has proved that APP and its breakdown products help to regulate lipid metabolism, including cholesterol levels.

Hartmann told BioWorld International: "This discovery is very important because it tells us the physiological regulatory cycle that we can target in order to try to prevent Alzheimer's disease." It also, he added, opens the door to preventing Alzheimer's disease by using existing lipid-regulating drugs, such as statins, or even by modulating diet and lifestyle to increase intake of certain types of fatty acids.

The group reported its work in the Oct. 9, 2005, issue of Nature Cell Biology in a paper titled "Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin."

In the brain of those with Alzheimer's disease, APP is sequentially cleaved, first by the enzyme b-secretase and then by g-secretase, to form amyloid beta peptide (Ab). There are two types of Ab, known as Ab40 and Ab42.

When Hartmann and his group began their study, they already knew much about those molecules, including many hints that they affected lipid metabolism. For example, earlier research had shown that if cholesterol levels were increased in experimental models of nerve cells, levels of Ab also would also increase. Other studies had demonstrated that cholesterol increased the activity of g-secretase, again with the result of increasing levels of Ab.

"But what we did not know," Hartmann said, "were the functions of all these proteins that were clearly involved in Alzheimer's disease. Everyone believed that APP would turn out to have a biological function, and that eventually we would discover what this was, but no one knew whether Ab had a biological function or if it was just a toxic waste product that somehow built up in Alzheimer's disease."

Hartmann and his team set out to investigate the link between Alzheimer's disease and lipid metabolism. They manufactured murine cells that lacked functional copies of the genes encoding g-secretase, and carried out tests to measure the levels and ratios of various lipids and lipid-metabolizing enzymes. Those allowed them to establish that the cells lacking g-secretase had significant damage to their normal control of lipid metabolism.

"We saw that g-secretase acts as a protease in lipid metabolism, cleaving APP, and it turned out that the product was Ab itself," Hartmann said.

The genetically engineered cells, which lacked expression of g-secretase, had twice the normal levels of cholesterol and of another lipid called sphingomyelin. The team's subsequent investigations into the control of levels of those molecules uncovered quite a complicated story.

They discovered that Ab42 down-regulates levels of sphingomyelin, while Ab40 down-regulates the production of cholesterol. "These findings made sense in several ways," Hartmann said. "First, since the cells produce Ab42 and Ab40 together, and sphingomyelin binds to cholesterol, this arrangement would serve to maintain the correct ratio of these two lipids within the cell. Secondly, in vascular dementia, it is common to find an accumulation of Ab40 in the blood vessels of the brain - and vascular dementia is commonly associated with high cholesterol levels."

Importantly, Hartmann added, the enzyme that is targeted by Ab40 during the process of down-regulating cholesterol synthesis is hydroxymethylglutaryl-CoA reductase (HMGR) - the same enzyme that is targeted by statins, the drugs that are used to treat hypercholesterolaemia.

Statins, he speculated, therefore may work as a treatment for Alzheimer's disease. "Initial studies by us and other groups have shown that statins given at the highest dose approved by the [FDA] to people with Alzheimer's disease have shown some benefit in improving cognitive performance. This needs further investigation. In the future, however, it may be possible to mimic the cholesterol-lowering effect of Ab40 with a molecule that would not cause Alzheimer's disease but which would decrease the activity of HMGR," Hartmann said.

Among other things, future investigations by his team will look at whether specific components of the diet, such as polyunsaturated fatty acids, might be able to reduce the risk of Alzheimer's disease by depressing plasma cholesterol levels.