Jefferson scientists help explain statins' effects in Alzheimer's disease

Scientists at Jefferson Medical College and the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia have taken another step in understanding the potential effects of anti-cholesterol drugs on Alzheimer's disease. They have identified a biochemical pathway that explains the activity of statins, particularly their ability to break down an early form of the protein amyloid that clusters and forms sticky plaques in the Alzheimer's brain.

The results may eventually help provide new targets for anti-amyloid drugs to help treat Alzheimer's disease. They report their findings Jan. 11, 2005 in the online journal the Public Library of Science Medicine.

Some epidemiological studies have found a link between people taking statin drugs to lower blood cholesterol and a lower incidence of Alzheimer's. Statins work by inhibiting an enzyme involved in cholesterol production, and currently is being tested in clinical trials for their possible effects in slowing the progression of Alzheimer's.

In a series of experiments, Sam Gandy, M.D., Ph.D., director of the Farber Institute for Neurosciences at Jefferson, Steve Pedrini, Ph.D., a postdoctoral fellow in Neurology in Jefferson Medical College of Thomas Jefferson University and in the Farber Institute for Neurosciences and their co-workers found evidence suggesting that an enzymatic pathway called Rho/ROCK may play an important role in the metabolism of APP (amyloid-beta peptide precursor protein), which is an early form of amyloid, and in turn, the ability of statins to break down a form of APP.

According to Dr. Gandy, APP can be broken down in two ways: "Bad cleavage" releases toxic amyloid-beta; "good cleavage" destroys it. Evidence shows that when the pathway ROCK1 is active, less good cleavage occurs. Statins, however, reduce ROCK1 activity, making it more likely that good cleavage will be in effect.

"It's particularly important to understand the pathways involved in Alzheimer's, especially to find more specific therapies," Dr. Pedrini says.

"This reveals an unsuspected pathway linking statins and amyloid metabolism," says Dr. Gandy. "This may help unravel statin action in Alzheimer's as well as point the way toward novel anti-amyloid drugs."

Dr. Gandy notes that the work is part of a developing anti-amyloid cocktail that may involve using several drugs, each aimed at a different target, not unlike chemotherapy for cancer. A drug called Alzhemed, for example, which currently is in clinical trials at Jefferson's Farber Institute for Neurosciences, breaks up amyloid aggregates. Vaccines stimulate the immune system to break down amyloid. Statins are yet another strategy.

---

---