For release: Wednesday, March 9, 2005
Studies have suggested that statins, a class of cholesterol-lowering drugs, may also lower the risk for Alzheimer’s disease (AD). A new study now suggests that some of the beneficial effects of the drug may be derived from a cholesterol-independent activity. This research, performed in mouse cells carrying an AD-causing gene mutation, may help scientists understand the clinical benefits of statins in AD.
Sam Gandy, M.D., Ph.D., director of the Farber Institute of Neurosciences of Thomas Jefferson University in Philadelphia, and his collaborators report for the first time that some effects of statins in AD may be due to the disruption of a chain of enzyme reactions that would normally lead to amyloid deposits, or plaques, in the brain. Amyloid deposits appear to be an early and critical event in Alzheimer’s disease. The study is published in the January 11, 2005, issue of the journal Public Library of Science Medicine and was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).
AD is characterized by the accumulation of amyloid plaques in the brain. In Alzheimer's, certain enzymes break down larger proteins in order to create the harmful amyloid-beta protein. This protein accumulates and forms sticky patches that are surrounded by the debris of dying nerve cells in the brains of Alzheimer's patients. Mice overexpressing the human amyloid precursor protein with a variation called the Swedish mutation (SweAPP) show age-dependent neural and cognitive alterations that resemble those described in AD patients. Dr. Gandy and colleagues used the SweAPP gene in mouse neuroblastoma cells to examine the effects of statins. The researchers found that two different statins inhibited the formation of amyloid-beta protein in the cells by preventing a chain of chemical interactions called the Rho/ROCK1 pathway. When the Rho/ROCK1 pathway is active, proteins are cut into “sticky” amyloid-beta deposits. However, when researchers added statin drugs or directly blocked the Rho/ROCK1 pathway, the proteins were broken down into harmless pieces.
“For the first time, we have identified a totally unsuspected pathway linking statins and amyloid metabolism,” says Dr. Gandy, “We have found a target that actively destroys and prevents the proteins that lead to plaques from ever forming. This research may help unravel statins’ action in Alzheimer’s as well as point the way toward novel anti-amyloid drugs.” Dr. Gandy’s future research will attempt to confirm the current findings in mature nerve cells in culture.
Numerous studies have pointed to a link between high cholesterol levels and an increased risk of AD. Similarly, investigators have reported a marked reduction in AD prevalence or risk in patients taking statins for the treatment of coronary artery disease, compared to individuals taking non-statin therapies or not receiving any treatment for this condition. Furthermore, a recently concluded clinical study showed that a statin slowed cognitive decline in AD patients compared to those receiving placebo. Statins’ ability to promote break down of amyloid proteins through the Rho/ROCK1 pathway suggests that statin treatment may benefit AD patients who have normal cholesterol levels as well as those with elevated levels of cholesterol.
Several clinical trials are investigating the possible role of statins in slowing the progression of AD. Investigators hope that this new understanding of the mechanism behind the clinical benefits of statins will lead to the development of more specific and effective drugs for patients with AD.
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: Pedrini S, Carter TL, Prendergast G, Petanceska S, Ehrlich ME, Gandy S. “Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK.” PLoS Medicine, January 11, 2005, Vol. 2 (1), pp. 69–78.
-By Michelle D. Jones-London, Ph.D.
Last Modified July 8, 2008