Protein Discovery Adds Clue To Solving Alzheimer’s Riddle

Apolipoproteins might essentially be viewed as “good guys” since their normal role in the human brain and body is to serve as “cholesterol busters,” that is, keep too much cholesterol from building up.

During the past several years, however, a particular apolipoprotein—Apolipoprotein E—has been indicted as a culprit in Alzheimer’s disease. Not only has a mutation in the gene that makes Apolipoprotein E been found to lead to Alzheimer plaque formation in the brain, but some half of all people who get late-onset Alzheimer’s have this mutation (Psychiatric News, August 18, 2000).

And now a “kissing cousin” of Apolipoprotein E—Apolipoprotein A-1—is also emerging as a possible player in Alzheimer’s, at least if basic research is any indication. The finding comes from John Lazo, Ph.D., a professor of pharmacology at the University of Pittsburgh School of Medicine, and his coworkers. It was reported in the March 27 Biochemistry, a peer-reviewed journal of the American Chemical Society.

Beta-amyloid—the major component of Alzheimer’s plaques—in turn derives from amyloid precursor protein in the brain. Thus, Lazo and his team wondered which of the some 300,000 proteins naturally present in the human brain and body might interact with amyloid precursor protein—that is, provide a fresh lead on Alzheimer’s causes. They decided to try to find out, using a technique that is officially called “yeast-to-hybrid screening,” but which informally, Lazo said in an interview, is referred to as “fishing—fishing for a protein partner.”

The researchers incorporated amyloid precursor protein into a yeast and exposed it to the 300,000 proteins naturally present in the human brain and body to see whether any of them would hook up with it. A few did, they found. One of them was Apolipoprotein A-1, or Apo-A for short. They found Apo-A’s affinity for amyloid precursor protein especially interesting for three reasons, Lazo explained.

For one, the binding appeared to be very tight, signaling that it might be especially important. For another, the attraction between Apo-A and amyloid precursor protein had not been reported before, or at least, as Lazo, clarified, “No one has ever used the approach that we used and seen this particular protein interaction.” And third, both Japanese and German investigators had reported clinical information suggesting that abnormally low levels of Apo-A in the brain and body might play a role in Alzheimer’s disease.

What transpires in a lab experiment, of course, is not necessarily what happens in humans or other animals. So a next step to demonstrate that inadequate Apo-A levels are involved in Alzheimer’s, Lazo said, might well be to test the concept in experimental animals. For instance, researchers could artificially raise Apo-A levels in the blood of mice that had been genetically engineered to express excessive amounts of beta-amyloid in their brains (that is, to mimic Alzheimer’s). Then the researchers could see whether this Apo-A increase decreased the beta-amyloid in the mice’s brains. In fact, Lazo said, he and his colleagues have the capability of conducting such an experiment and have placed it at the top of their priority list.

If such an animal experiment were to indeed suggest that raising blood levels of Apo-A might counter beta-amyloid in the brain, the next step, Lazo said, might be to see whether increasing levels of Apo-A in the blood of Alzheimer’s patients might help them.

What is especially appealing about this idea, Lazo pointed out, is that people can raise the Apo-A levels in their blood simply by changing their diets, and foods that have shown promise as Apo-A boosters are fruits, soybeans, coconut oil, some wines, and some teas.

The study report by Lazo and his team, “Apolipoprotein A-1 Directly Interacts With Amyloid Precursor Protein and Inhibits Amyloid-Beta Aggregation and Toxicity,” is accessible online at www.pubs.acs.org/subscribe/journals/bichaw/browse.html on a pay-per-view basis to nonsubscribers. ▪