A new approach to controlling blood cholesterol levels that is already being investigated to prevent cardiovascular disease also may be a potential treatment for Alzheimer's disease.
In their report in the October 14 issue of Neuron, researchers from Massachusetts General Hospital (MGH) show that blocking a pathway that controls the distribution of cholesterol in cells dramatically reduces the number of amyloid plaques in the brains of transgenic mice. Some of the treated mice were much better at learning their way through a maze than were untreated mice.
"We found that this way of reducing cholesterol levels in the brains of living animals both decreased amyloid deposition and improved learning," says the study leader Dora Kovacs, PhD, director of the Neurobiology of Disease Laboratory in the Genetics and Aging Research Unit of MassGeneral Institute for Neurodegenerative Disorders. "As far as we know, this is the first study of cholesterol metabolism's impact on amyloid levels that included cognitive testing."
Researchers have been investigating a potential relationship between cholesterol metabolism and Alzheimer's since it was found that a particular variant of the gene for a protein called apoE significantly increased risk of the disease. Since the apoE protein transports cholesterol, that discovery suggested that disruption of cholesterol handling might cause or worsen the development of the amyloid plaques that characterize Alzheimer's disease. In addition, some epidemiologic studies have suggested that people taking statin drugs to control blood cholesterol have a reduced incidence of Alzheimer's.
In 2001 Kovacs' team showed in cells that the activity of an enzyme called ACAT, which controls whether cholesterol is stored in the cellular membrane or in intracellular droplets, also appears to regulate the formation of amyloid-beta, the protein fragments that make up amyloid plaques. The current study was designed to test that same approach in living animals.
At first, researchers tested whether the ACAT inhibitor used in the 2001 study would affect cholesterol storage in brain cells of mice. Because ACAT inhibitors are metabolized quickly, the researchers used implantable pellets that release the compound in a steady manner and found that the inhibitor significantly reduced the number of cholesterol droplets in brain cells of normal mice.
They then implanted inhibitor pellets in mice with a human gene that leads to amyloid plaque formation. Examination of brain tissue after two months of treatment found that mice receiving the ACAT inhibitor had 90 percent less plaque than did transgenic mice who received placebo pellets. The results were even more dramatic in female mice, who usually develop plaques earlier than males do. Biochemical analysis of mouse brain tissue showed that the inhibitor probably prevents amyloid-beta production, rather than reducing its deposition.