Nitric oxide inhibition slows Alzheimer's disease in mice, Weill Cornell team reports

NEW YORK -- A toxic gas appears to speed neurological decline in mice bred to mimic Alzheimer's disease, and inhibiting the production of this gas -- called nitric oxide -- led to dramatic slowdowns in the rodents' disease-related brain damage, according to a new study by researchers at the Weill Medical College of Cornell University.

"The findings are preliminary, but drug companies have already developed agents that may safely inhibit the disease-associated form of the enzyme responsible for producing nitric oxide in the human brain. Our hope is that the results seen in this mouse study might someday be replicated in humans," said lead researcher Dr. Carl Nathan, R.A. Rees Pritchett Professor of Microbiology and Chairman of the Department of Microbiology and Immunology at Weill Cornell Medical College.

Reporting in the November 7 issue of The Journal of Experimental Medicine, the Weill Cornell team focused their efforts on nitric oxide, which scientists only recently discovered plays a role in the biology of most living organisms.

"This gas is produced by three enzymes. Where the brain is concerned, the culprit we looked at is an enzyme called iNOS," said study senior author Dr. Flint Beal, who is the Anne Parrish Titzell Professor of Neurology and Chairman of the Department of Neurology and Neuroscience at Weill Cornell, as well as Neurologist-in-Chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

The "i" in iNOS (so named by Dr. Nathan after its discovery in 1992) stands for "inducible." "It's an enzyme that is induced into action to produce nitric oxide during infection, inflammation, or an immune response," Dr. Nathan said.

As such, iNOS has no place in the healthy brain, but scientists have long noticed high levels of the enzyme in the brains of Alzheimer's patients.

"It shouldn't be there -- it seems to be causing trouble without providing any benefit," Dr. Beal said.

He and Dr. Nathan suspected that an abnormal form of a protein called amyloid-beta -- a hallmark of Alzheimer's disease -- may serve as an irritant, "fooling" the body into thinking that an infection-like process is underway, and spurring iNOS to begin producing nitric oxide.

They also suspected that rising concentrations of nitric oxide in the brain accelerate Alzheimer's disease progression.

To examine this, the research team tracked the health of two strains of mice, both genetically engineered to mimic human Alzheimer's disease. Half of the mice were further genetically altered to lack iNOS, while the other half retained usual iNOS expression.

"While both groups of mice early on developed brain lesions suggestive of Alzheimer's-like illness, mice without iNOS had much slower disease progression compared to those with iNOS expression," Dr. Nathan said.

If these findings in mice apply to people, then inhibiting iNOS activity -- and related nitric oxide production -- could be a new and powerful means of slowing Alzheimer's disease.

"Stopping iNOS wouldn't cure Alzheimer's, because iNOS expression is not the cause of the disease. But inhibiting the enzyme might slow disease progression considerably -- much more effectively than any agents we have now," Dr. Beal said.

The researchers note that many drug companies have already developed iNOS inhibitors as potential treatments for inflammatory disorders such as multiple sclerosis or rheumatoid arthritis. And since the body only requires iNOS to fight off serious infection, "iNOS inhibitors might be safe for most patients -- excepting during certain infections, such as tuberculosis," Dr. Nathan said.

The next step, according to the researchers, is to test iNOS inhibitors in a mouse model under conditions that are closer to human Alzheimer's disease.

"In this study, iNOS was genetically inhibited before the mice developed Alzheimer's," Dr. Beal explained. "Of course, that wouldn't happen in human cases. So in our next study, also in mice, we'll watch what happens when we use a drug to inhibit normal iNOS expression in mice after the signs of Alzheimer's begin to appear. That's much closer to what would happen in a clinical setting, when a patient develops symptoms and comes to a physician for treatment."

That study, to be funded by the Dana Foundation, will be a collaboration between Drs. Beal and Nathan of Weill Cornell, and Dartmouth College researcher Dr. Michael Sporn.

The Weill Cornell experts cautioned that this line of research is in its infancy, and the journey from mouse studies to clinical applications at the bedside can take years to complete, if it happens at all.

"The degree of the effect that we are seeing in these mice, if it proves relevant to humans, is greater than what people have seen with any other chemical inhibition in mice," Dr. Beal said. "It gives us hope."

The study was funded by grants from the National Institutes of Health, the Alice Bohmfalk Charitable Trust, and the Robert Leet and Clara Patterson Trust.

Co-authors include Dr. Noel Calingasan, Jon Nezezon, Dr. Aihao Ding, Dr. Krista La Perle, Michele Fuortes, Dr. Michael Lin, Dr. Sabine Ehrt, Dr. Nyoun Soo Kwon, Dr. Junyu Chen, and Dr. Khatuna Kipiani -- all of Weill Medical College of Cornell University; Dr. M. Scott Lucia, of the University of Colorado Health Sciences Center, Denver; and Dr. Yoram Vodovotz, of the University of Pittsburgh.

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