Increasing levels of a protein that helps the brain use cholesterol may slow the development of Alzheimer’s disease changes in the brain, according to School of Medicine researchers studying a mouse model of the disease.
Elevated levels of the protein ABCA1 sharply reduced buildup of brain plaques that are a hallmark of Alzheimer’s disease, according to senior author David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of the Department of Neurology at the School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital.
The study, appearing this month in The Journal of Clinical Investigation, highlights a new possibility for potential Alzheimer’s treatment: altering the brain’s use of lipids, a class of fat-soluble compounds that includes cholesterol.
“It’s becoming clear that ABCA1 may be a good drug target for Alzheimer’s therapies,” Holtzman said. “There are known drugs that can increase ABCA1 levels, and with some further development of this or similar classes of drugs and additional insights into how ABCA1 slows down plaque deposition, there may be a way to create a new approach to Alzheimer’s treatment.”
Discovered in 2001, ABCA1 is a naturally occurring enzyme already under study for its potential to treat heart disease. Lipids like cholesterol aren’t soluble, so to be transported through the bloodstream and into and out of cells and organs, they have to be associated with molecules known as apolipoproteins. ABCA1 facilitates this process, which is known as lipidation.
In the circulatory system, ABCA1 lipidates HDL (high-density lipoprotein) with cholesterol to form fully functioning HDL, the “good” cholesterol thought to decrease risk of heart disease. Cardiovascular researchers are testing drugs that increase ABCA1 levels, hoping eventually to use them to prevent or alleviate atherosclerosis, or hardening of the arteries.
Holtzman said he was intrigued by the connection between ABCA1 and lipidation because a primary risk factor for Alzheimer’s disease is an apolipoprotein known as apoE. Different genetic forms of apoE are linked to significant changes in an individual’s risk of developing late-onset Alzheimer’s disease.
In earlier research, Holtzman’s lab revealed that ABCA1 also lipidates good cholesterol in the brain. When they used mice lacking the gene for ABCA1 and bred them to a mouse model of Alzheimer’s disease, the animals developed a much great number of the brain plaques characteristic of the disease.
For the new experiment, Holtzman laboratory members Suzanne Wahrle Schindler, an M.D./Ph.D. student, and Hong Jiang, a senior research technician, created a line of mice genetically altered to make unusually high levels of ABCA1 in the brain. When they crossbred that line with their Alzheimer’s disease mouse model, they found that mice with high ABCA1 levels built up plaques in their brains much more slowly and to a much lesser extent than those with normal ABCA1 levels.
The work showed that ABCA1 is facilitating the lipidation of HDL and apoE. Holtzman’s theory is that this allows apoE to better scavenge amyloid beta, the main ingredient of plaques, from the brain in a way that decreases the chances that plaques will begin to form. An earlier experiment by other scientists showed that lipidated apoE binds more tightly to soluble amyloid beta than non-lipidated apoE. Further research, however, is needed to prove this theory.
A class of drugs is already available that increases ABCA1 levels: LXR (liver X receptor) agonists. Holtzman stressed that these drugs need to be fine-tuned to avoid an undesirable side effect that increases fat buildup in the liver.