Two Sides to Abeta

Posted: Jan. 21, 2012

For the last 27 years, Abeta, a fatty protein that is created in the brain, has been identified as the leading cause of Alzheimer’s disease. As a result, the majority of efforts aimed at developing a cure have targeted Abeta as the enemy. But recent studies have indicated that simply wiping out Abeta in the brain is not the solution.

Everything in moderation

While too much rain can cause flooding, not enough can cause a drought. Yet nature depends on rain for its very existence. Similarly, studies have shown that Abeta, previously thought to be an unequivocal “bad guy” in Alzheimer’s pathology, may play a pivotal role in the brain.

“Too much Abeta in the brain acts like a plugged-up kitchen sink,” explains Rudy Tanzi, Ph.D., Harvard Medical School/Massachusetts General Hospital and chairman of Cure Alzheimer’s Fund Research Consortium. Treating an overabundance of Abeta means either slowing production (fixing the leak) or hastening clearance (unclogging the drain).

“Too much Abeta creates plaques and tangles, which kill brain cells, choke synapses, impair cognition and lead to Alzheimer’s,” says Tanzi.

On the other hand, explains Robert Moir, Ph.D., Harvard Medical School/Massachusetts General Hospital, “not enough Abeta can impair the body’s natural immune system.” In its non-toxic form, Abeta appears to be a vital antimicrobial peptide (a portion of a protein) that protects the body from deadly infections. In fact, one experimental drug that eradicated Abeta in the brain led to meningitis, a deadly side effect.

In finding a cure for Alzheimer’s, researchers are working to determine how to keep Abeta production at safe levels without completely wiping it out, which makes drug discovery that much more complex.

Statins

When scientists first discovered that too much cholesterol in the blood caused heart disease, high cholesterol became the target. But scientists also learned that while an overproduction of LDL (low-density lipoproteins) is life-threatening, HDL (high-density lipoproteins) are important for keeping people healthy. Like Abeta, eliminating cholesterol completely was not the answer.

As a result, scientists developed statins, such as the drug Lipitor, to reduce the risk of heart disease. By controlling cholesterol production, cases of heart disease have dropped substantially. “We need the equivalent of a ‘statin’ for Alzheimer’s disease,” says Tanzi.

Today, Cure Alzheimer’s Fund is funding research on a class of drugs called gamma secretase modulators involved in the production of Abeta—to modulate production within tolerable limits without eliminating it altogether—the same type of function that statins perform for cholesterol. The goal is to develop a drug that can lower the incidence of Alzheimer’s the way statins did for heart disease.

Taking control of Alzheimer’s through research

At Cure Alzheimer’s Fund’s symposium in October, Tanzi and Moir discussed both the dangers and benefits of Abeta. Moir acknowledged the importance of CAF’s funding in the work toward finding a cure.

“The public funding environment is so risk-averse that you can’t get funding for critical, cutting-edge research, which is what we need to get to a cure,” he says. Tanzi adds, “Without CAF support, we might never have known, or not known for a long time, that Abeta may be performing a beneficial or even vital role when its production and clearance are balanced effectively in the brain.”

Tanzi adds that, “While CAF has provided tremendous support for research, we still need more. With the funding we have today, we can only tackle 2 to 5 percent of our top priorities. Alzheimer’s disease is unique in that it’s not science constrained, it’s budget constrained.”

One thing is certain

The “two sides of Abeta” demonstrate clearly the importance of basic research for the development of truly effective therapies. Drugs based on just one understanding or the other will not work effectively and may even prove to be harmful. But finding a cure requires both time and money, neither of which there is enough of today.

Since we can’t control time, the threat looming over the 71 million baby boomers headed toward the high-risk ages for Alzheimer’s disease makes funding more critical than ever.