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 Aß 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 Aß 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 significant cognitive benefit for AD patients with normal serum cholesterol."
Although CP-113,818 has not been tested in clinical trials, another ACAT inhibitor, avasimibe, developed by Pfizer, is now in final clinical trials as a treatment for vascular disease and atherosclerosis. That drug is "considered safe for human use, with a good therapeutic window," wrote Kovacs and her colleagues.
"Our results suggest that slow-release biopolymer administration of ACAT inhibitors may be considered as a potential strategy for the treatment and prevention of Alzheimer's disease, alone or in combination with statins," they wrote.
Birgit Hutter-Paier, Henri J. Huttunen, Luigi Puglielli, Christopher B. Eckman, Doo Yeon Kim, Alexander Hofmeister, Robert D. Moir, Sarah B. Domnitz, Matthew P. Frosch, Manfred Windisch, and Dora M. Kovacs: "The ACAT Inhibitor CP-113,818 Markedly Reduces Amyloid Pathology in a Mouse Model of Alzheimer's Disease"
Published in Neuron, Volume 44, Number 2, October 14, 2004, pages 227–238.
Journal
Neuron