Better Healthcare

Winter 2013
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by Elizabeth Gardner

Two DePaul researchers are working on small mysteries that may help solve the larger mystery of Alzheimer’s disease, perhaps the most dreaded diagnosis in modern medicine. It’s the sixth-leading cause of death in the U.S., after heart disease, cancer, chronic lower respiratory diseases, stroke and accidents. It’s the only one of those that we can’t prevent, cure or slow down. And it kills the mind–what makes us ourselves–before killing the body, taking a terrible toll on patients and their families. A few drugs help with symptoms, but the cause, cure and prevention of Alzheimer’s disease is one of the most compelling and urgent missions in medical research.

Eric Norstrom, assistant professor of neurobiology, and Sandra Chimon-Peszek, assistant professor of chemistry, study different aspects of proteins associated with Alzheimer’s disease. Proteins–complex molecules that play indispensable roles in every function of our cells–can malfunction with disastrous results. In general, drugs work by acting on proteins, and discerning their exact role in a disease is essential to finding effective treatments.

When proteins don’t do what they should, it’s often because they’re the wrong shape. Proteins are long chains of amino acids that fold in on themselves in intricate ways to form functional molecules. Their effects in the body can change dramatically depending on how they fold. Amyloid proteins have folded inappropriately and formed stiff, insoluble fibers. They’re implicated not only in Alzheimer’s disease, but also in Type 2 diabetes, Parkinson’s disease, Huntington’s disease, atherosclerosis and rheumatoid arthritis, to name a few.

Chimon-Peszek studies how mutations in amyloid proteins affect the way they fold and at what point “misfolding” causes toxic effects on the brain. Even a change in a single gene pair out of millions can turn a healthy protein into a toxic one, and identifying those mutations is a large part of her research. Her group also investigates various natural substances, such as curcumin, turmeric, melatonin and milk thistle, to see how they affect the neurotoxicity of amyloid proteins.

She employs a small army of undergraduates–23 at last count–along with one or two graduate students. The undergraduates can do short projects in as little as 10 weeks that give them a taste of the research life and make a meaningful contribution to the larger project.

Chimon-Peszek says the final, fibrous stage of the amyloid proteins is not the most damaging part, even though it’s the one most evident in the brains of Alzheimer’s patients. The proteins have an intermediate phase, called the “beta sheet” stage, where they can form spheres or multi-globular structures that look like brown balls. The spheres are soluble and able to enter the cells in the brain. The sphere kills off the cell and then forms the fiber that’s the hallmark of Alzheimer’s. The fibers can kill brain cells, too, but they’re not as deadly as the spheres.

“What we want to do is not just prevent the folding, but also prolong the state at which these beta sheets form,” she says. “We’d like to bypass that spherical stage because the fiber stage isn’t as toxic. People would still get the disease, but they’d get it later with less detrimental effect.”

Her group is also testing a number of natural substances that might slow down cell death from the harmful proteins. “These are all hearsay items, where people have said ‘my mom takes this and thinks it helps,’” she says. “Curcumin is an anti-inflammatory and used for stomach aches, and it’s been shown to slow the process [of Alzheimer’s-like cell death] anywhere from 10 to 50 years in the test tube.” They’ve seen some effects from all the natural products they’ve tried, including curcumin, rosemary, apricot seeds and melatonin. They’re now trying milk thistle extract and expect to experiment on vitamin B-12 soon.

Norstrom is studying the molecular function of amyloid precursor protein (APP), a common protein in the brain. Usually it causes no problems, but in Alzheimer’s patients, it interacts with certain other proteins and metabolizes to form beta amyloid peptide, the main component of the brain deposits that characterize Alzheimer’s.

Norstrom is looking for the proteins that interact with APP and cause it to take the “disease” path rather than its normal one. Once the peptide takes hold, it’s difficult to change it without jeopardizing brain function. “By the time Alzheimer’s presents, there’s already been a lot of damage,” Norstrom says, because the symptoms are evidence that the brain has run out of ways to adapt to the disease. However, APP plays an important role in normal brain functioning as well, and altering its metabolism may have its own unwanted side effects. “It’s best to know as much as you can about APP’s lifetime within the cell,” Norstrom says.

Norstrom worked on prion diseases like mad cow disease as a graduate student and has always been interested in how molecular machinery goes awry. In his post-doctoral studies at the University of Chicago, he created a mouse with a genetic alteration specifically for looking at protein interactions related to Alzheimer’s and used it to identify proteins that could be important.

Norstrom says small labs like his and Chimon-Peszek’s can play a key role in biomedical research by finding interesting niches and publishing clues for larger labs to follow up on. “I can’t compete with giant labs, so I need to be more wily and clever at what I look at,” he says. “We have found interesting novel proteins that aren’t something a large lab can attack with brute force.”

Norstrom says he hopes the scientific community will take up any discoveries that his lab contributes. He recognizes that it’s a long road: first reproducing the original results multiple times at the cellular level, then animal testing to see if they translate to the level of a complex organism, and then the grueling and expensive process of developing a safe, effective drug and conducting clinical trials.

“No single lab could discover something and then bring it all the way to the bedside,” he says. “But I’d love to be able to say I discovered a protein interaction that can bias metabolic pathways and slow or cure disease.”

Freelance writer Elizabeth Gardner has covered science, business and technology topics for such publications as University Business, Internet Retailer and Modern Healthcare. She is based in Chicago.