CP-113,818 mimics a cholesterol molecule that the enzyme, called "acyl-coenzyme A: cholesterol acyltransferase" (ACAT), converts into a form of cholesterol that the cell stores in droplets. When CP-113,818 is administered, it plugs into the "active site" of ACAT, jamming its operation and preventing the enzyme from processing cholesterol.
Cholesterol is required in the production of the short protein called A peptide, the building block for the amyloid plaque that clogs the brain in Alzheimer's disease, ultimately killing brain cells. In the mouse experiments, the researchers administered CP-113,818 by implanting slow-release biopolymer pellets under the skin of both normal mice and transgenic animals engineered to have the human form of the aberrant protein that leads to A peptide. Such transgenic mice develop the hallmark pathology of Alzheimer's, including brain amyloid plaque and memory deficits.
The researchers found that treatment of the normal mice markedly reduced the levels of the storage form of cholesterol in their brains. And in the transgenic animals, the treatment reduced the accumulation of amyloid plaque by 88%99% percent and reduced the storage form of cholesterol by 86%. When the researchers tested the treated versus untreated animals, they found a slight improvement in the animals' ability to learn and remember the location of a submerged platform in a water tank--a standard test of learning and memory.
Cholesterol-lowering statins are now being tested as a means of reducing the risk of Alzheimer's, said the researchers, although "It remains to be shown that statins can provide signi
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
13-Oct-2004