Monday, September 4, 2006

FROM THE LAB.3 - Sept. 2006

by Dr. Malcolm Leissring, Scripps Florida

Q: How is beta-amyloid cleared from the brain?
A: Primarily by enzymes known as proteases that cut beta-amyloid into pieces.

In previous entries to this series, we showed that the central culprit in Alzheimer’s disease is beta-amyloid, a short protein fragment that has a pronounced tendency to stick to itself, forming toxic aggregates that eventually accumulate into the plaques that litter the brains of Alzheimer’s disease patients. By using the analogy of an overflowing kitchen sink, we also described two fundamental strategies for combatting the disease: (1) inhibiting the production of beta-amyloid (“turning down the faucet”), and (2) boosting the clearance of beta-amyloid after it is produced (“unclogging the drain”).

This month, we delve a bit deeper into the unclogging-the-drain approach by briefly introducing several enzymes that are primarily responsible for clearing beta-amyloid. These enzymes work by cutting beta-amyloid into pieces, and are called “proteases.” As we mentioned in previous posts, the importance of these proteases to Alzheimer’s disease was recognized only recently. This is a highly significant development, because each of these enzymes represents a new target for the development of drugs. Before, most drug research was focused on only two principal targets (the secretases that are responsible for producing beta-amyloid), but now have over a dozen targets to investigate, significantly increasing the chances that we will find at least one drug to combat this terrible disease.

Our lab is especially interested in one particular protease named insulin-degrading enzyme. Next month we will expand on the reasons why this is a particularly attractive target. We also hope to announce a very significant advance in our understanding of insulin-degrading enzyme and its potential as a therapeutic target that is expected to be published in the prestigious scientific journal Nature in the coming weeks.

For the moment, we will limit ourselves to simply listing some of the proteases that are known to degrade beta-amyloid, with short descriptions of their potential therapeutic value.

Insulin-degrading enzyme. As its name suggests, this protease also cleaves insulin, and it has been implicated in both Alzheimer’s disease and also diabetes. This is significant because having diabetes can increase your risk of developing Alzheimer’s disease, suggesting that defects in this protease might underlie both diseases. As we will describe next month, a considerable amount of research suggests that insulin-degrading enzyme is an especially attractive therapeutic target.

Neprilysin. This is by far the best characterized beta-amyloid protease. Our group showed that increasing the activity of this protease can completely prevent Alzheimer’s disease in a mouse model of the disease. This does not, however, mean that the other proteases are less important—we were simply lucky enough to get very large increases in this protease in our experiment. It is very likely that increasing the activity of any beta-amyloid protease can achieve the same effect.

Endothelin-converting enzyme. This protease was shown to degrade beta-amyloid by Chris and Elizabeth Eckman, our close collaborators at the Mayo in Jacksonville, FL. Recent evidence has identified fragments of beta-amyloid in human brains that appear to match the fragments generated by this protease, suggesting it might be especially important in the normal degradation of beta-amyloid.

Plasmin. This protease, found principally in the blood stream, is involved in the degradation of blood clots. There are several exciting things about this protease. First, unlike the preceding proteases, it can cut beta-amyloid even after it has started to clump together. Second, it is normally inhibited by another protein called PAI-1. This is important because plasmin can be easily activated by drugs that block the plasmin-PAI-1 interaction. Indeed, this very approach is being pursued by scientists at Wyeth, and they have shown that their drugs can slow Alzheimer’s disease in mice.

Matrix-metalloproteases (MMPs).
A mouthful, I know, but these are an important class of about 15 related proteases. Recent studies have shown that certain MMPs can cleave beta-amyloid, even after it has clumped together. As was true for plasmin, these proteases can be turned on and off, making it possible to develop drugs that do the same thing. A potential problem is that excessive MMP activity is associated with arthritis and cancer, making it potentially unwise to target these for the treatment of Alzheimer’s disease.

Angiotensin-converting enzyme (ACE).
This protease is involved in the regulation of blood pressure. It has recently been shown to cleave beta-amyloid in cells and in mice, and there is genetic evidence that implicates this protease in Alzheimer’s disease. Importantly, millions of people use ACE inhibitors, which could conceivably affect their risk for Alzheimer’s.

As you can see, this is already a long list of proteases, and unquestionably it will get longer still with further research. The longer, the better, of course, since any one of these proteases might hold the key to a cure for this mind-robbing disease.

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