iNOS inhibitors may be effective therapies for Alzheimer's disease

Nov 1 2005

A noxious gas speeds up brain degeneration in Alzheimer's disease, according to a study in the November 7 issue of The Journal of Experimental Medicine.

Carl Nathan and colleagues at Cornell University Weill Medical College found that an enzyme that triggers the production of nitric oxide (NO) -- a gas that helps immune cells fight off invading pathogens -- accelerates the formation of brain lesions in Alzheimer's-prone mice.

The study suggests that inhibitors of this enzyme (called iNOS) -- which have already been produced and tested in humans -- might be a promising and thus far overlooked therapy for the treatment of this devastating disease.

Alzheimer's disease is a lethal neurodegenerative disease that causes progressive memory loss and dementia. The disease is associated with a build-up in the brain of abnormal fragments of a resident brain protein called beta-amyloid protein. Researchers have not yet figured out exactly how the fragments of this protein (referred to as A-beta) cause disease, but they have some clues.

One clue is the fact that A-beta causes brain cells to make iNOS. This enzyme is normally turned on during infection and is needed to help immune cells destroy invading pathogens. But iNOS is not normally found in the brain. There, the enzyme may cause cellular damage that destroys neurons.

For nearly a decade, researchers have known that iNOS was present in the brain lesions of patients with Alzheimer's disease, but nobody had addressed whether its presence was making the disease worse. Nathan and colleagues now show that Alzheimer's-prone mice that lack iNOS live twice as long and develop fewer brain lesions than iNOS-expressing mice. Both groups of mice developed some brain lesions initially, but the iNOS-deficient mice were spared the rapid accumulation of lesions later in life.

Based on these results, Nathan suggests that iNOS inhibitors might turn out to be more effective than current therapies for Alzheimer's disease, which temporarily improve performance on cognitive tests, but do not increase survival.

http://www.jem.org/