Disarming Alzheimer’s Toxic Proteins

A new study of the proteins that may be responsible for the brain lesions associated with Alzheimer’s disease promises a new understanding of its underlying cause, and may someday yield new treatments for the devastating and deadly disease.

Results of the study, reported here today at a meeting of the American Chemical Society, reveal a potential new pathway to understanding and treating Alzheimer’s, a disease of the brain that afflicts 4 million Americans and for which there is now no definitive treatment and no cure.

Alzheimer’s, which usually afflicts people over age 65, manifests itself through progressively impaired memory, leading to mental confusion as the disease systematically destroys the brain one cell at a time.

The new study, conducted by Regina M. Murphy, a University of Wisconsin–Madison professor of chemical engineering, and Laura L. Kiessling, a UW–Madison professor of chemistry, reveals a way to disrupt the aggregation of proteins that form the poisonous plaque deposits found in the brains of Alzheimer’s patients.

The plaques associated with Alzheimer’s are composed mostly of beta amyloid fibrils, small sticky protein molecules that, when clumped together, form toxic tangles of proteins that some scientists believe may be the root cause of Alzheimer’s pathology.

“The protein sticks to itself,” says Kiessling, and forms poisonous clumps that, along with dead and dying nerve cells, become the raw material for the plaques that form around and between nerve cells. The plaques, which first appear in the part of the brain responsible for memory and cognition, are believed to erode nerve endings and thus interfere with the normal processes of the brain.

Although the toxicity of the bundles of beta amyloid proteins is well documented, it has not been definitively demonstrated that they are responsible for Alzheimer’s pathology. What is known is that when the proteins begin to clump, they become toxic, making them prime suspects in the case of Alzheimer’s pathology.

Murphy, who studies protein aggregation, and Kiessling, an expert on inflammation, wondered if it might be possible to disrupt the protein aggregation process by synthesizing specific “inhibitor molecules” that could bind to the beta amyloid protein and thus prevent it from forming the toxic aggregates.

So far, that strategy seems to be working, says Kiessling: “It’s a really simple idea and, as far as we know, there are few strategies that target this step in the process.”

The beta amyloid protein molecules are composed of amino acids arrayed in a set sequence. By engineering synthetic molecules that have a beta amyloid binding region attached to a disrupting region, the Wisconsin scientists have generated compounds that successfully block the toxicity of beta amyloid in cell culture. In essence, using synthetic molecules to alter the structure of the protein aggregates, the scientists have found a way to detoxify the protein clumps that might otherwise kill or damage nerve cells.

“I see this as an important first step toward trying to find out how important the toxicity of beta amyloid proteins is,” says John Cross, chief scientist for the American Health Assistance Foundation which supported the work by Kiessling and Murphy. Based in Rockville, Md., the foundation will spend more than $1.6 million on Alzheimer’s research this year in addition to other programs of medical research.

Murphy and Kiessling say the advantages of their strategy lie in the precise targeting of the proteins believed responsible for the disease’s pathology, and in the apparently simple tactic of disrupting the process of protein aggregation.

The scientists cautioned that while the approach seems promising as a way to understand and someday treat one of the nation’s most prevalent and devastating diseases, the work is still preliminary.

Further tests in animals and humans are required, and the significant problem of designing molecules small enough to pass through the blood-brain barrier — a primary line of natural defense for the brain — remain.

However, if subsequent studies affirm the potential of designing customized molecular inhibitors that can defang the poisonous proteins associated with Alzheimer’s, new, more effective medicines may emerge within the next decade.

CONTACT: Regina M. Murphy (608) 262-1587, murphy@che31a.che.wisc.edu; Laura L Kiessling (608) 262-0541, kiessling@chem.wisc.edu