For release: Friday, January 14, 2005
A drug designed to inhibit cholesterol production may also block the production of amyloid, a hallmark of Alzheimer’s disease (AD). In a mouse model of the disease the drug CP-113,818 reduced amyloid buildup by up to 99 percent and worked for up to 2 months without any evidence of toxicity. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).
CP-113,818 was previously shown to reduce amyloid in nerve and other cells. The drug inhibits the cholesterol-modifying enzyme ACAT (acyl-coenzyme A:cholesterol acyltransferase) that allows the buildup of amyloid. In the current study, investigator Dora M. Kovacs, Ph.D., director of the Neurobiology of Disease Laboratory at Massachusetts General Hospital and colleagues in the U.S. and Austria tested the hypothesis that ACAT inhibition would also inhibit the amyloid-beta peptide involved in AD.
The researchers first tested the drug on 18 non-transgenic mice over 21 days using different dose levels of slow-release pellets that were surgically inserted under the skin. The investigators studied dose levels ranging from 0.2 to 7.1 mg/kg per day. At the highest daily dose given, CP-113,818 reduced total cholesterol levels by 29 percent without any apparent effect on food consumption or body weight. Hepatic free cholesterol and cholesteryl-esters also decreased dramatically at lower doses, in a dose-dependent manner.
Slow-release pellets containing a 60-day supply of the highest dose of the drug per day were then surgically inserted under the skin of 12 mice specially bred to carry various forms of familial AD. Twelve control mice received a placebo pellet. The study was halted just before 2 months to ensure continued release of the drug. The scientists found no evidence of toxicity in mice receiving the drug and blood cholesterol levels were reduced to levels similar to normal mice.
Amyloid plaque was reduced by 88 percent in brain tissue in mice who received CP-113,818 and up to 99 percent in the hippocampus of the female transgenic mice. These findings, together with chemical analyses conducted on the mouse brains, suggest that the ACAT inhibitor prevents accumulation of newly formed plaques and is highly effective in reducing the amount of plaque already there.
The treated mice also performed better in a test of cognitive function.
Although CP-113,818 is not optimal for clinical testing in humans, a similar ACAT-inhibiting drug, CI-1011, is currently in phase III trials for vascular disease and atherosclerosis.
Researchers have previously shown that statin drugs (or statin-like compounds) can dramatically reduce amyloid pathology in different animal models when administered before amyloid begins to accumulate.
“Our findings suggest that slow-release administration of ACAT inhibitors may be a novel strategy to treat and prevent AD, either alone or in combination with statins,” said Dr. Kovacs.
Diane Murphy, Ph.D., an NINDS program director for neurodegenerative disorders, said "Although much more work is needed before these inhibitors can be tested in humans, this study is a promising and exciting first step in determining if ACAT inhibitors could be given to patients to reduce amyloid in Alzheimer’s disease.”
The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation’s primary supporter of biomedical research on the brain and nervous system.
Reference: Hutter-Paier B, Huttunen HJ, Puglielli L, Eckman CB, Kim DY, Hofmeister A, Moir RD, Domnitz SB, Frosch MP, Windisch M, Kovacs, DM. “The ACAT Inhibitor CP-113,818 Markedly Reduces Amyloid Pathology in a Mouse Model of Alzheimer’s Disease.” Neuron, Vol.44, Issue 2, October 14, 2004.
-By Paul Girolami, NINDS Office of Communications and Public Liaison
Last Modified March 1, 2007