October 15, 2004

New way of controlling cholesterol may help treat Alzheimer's

A new approach to controlling blood cholesterol levels already being investigated to prevent cardiovascular disease also may be a potential treatment for Alzheimer's disease. In their report in the Oct. 14 issue of Neuron, MGH researchers 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.

"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.

Researchers have been investigating a potential relationship between cholesterol metabolism and Alzheimer's for several years. Previous research by Kovacs' team showed that an enzyme called ACAT, which controls where cholesterol is stored in cells, also appears to regulate the formation of amyloid-beta, the protein fragments that make up amyloid plaques.

In the current study, pellets containing a drug that inhibits ACAT activity were implanted in mice with a human gene that leads to amyloid plaque formation. After two months of treatment, mice receiving the ACAT inhibitor had 90 percent less plaque in their brain tissue than did transgenic mice who received placebo pellets. In addition, transgenic mice that received the inhibitor were much more successful in learning their way through a maze than were those that received the placebo.

While the particular ACAT inhibitor used in this study is not yet appropriate for human trials, others have been proven safe in clinical trials. Kovacs' team has begun studying one of these for possible Alzheimer's application. Her MGH collaborators are co-first author Henri Huttunen, PhD; Luigi Puglielli, MD, PhD; Doo Yeon Kim, PhD; Robert Moir, PhD; Sarah Domnitz; and Matthew Frosch, MD, PhD.