page 1163. Nathan and colleagues show that the NO-producing enzyme iNOS accelerates brain destruction and death in a mouse model of Alzheimer's 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 peptide fragments derived from a protein called β-amyloid precursor protein (APP). APP is a protein that normally gets cleaved in the brain, although the functions of APP and of its primary cleavage products are poorly understood.
Mutations in APP, or in the enzymes that chop it up, result in the overproduction of the disease-causing peptide (known as Aβ). Although it is not completely clear how Aβ contributes to disease, it has been shown to trigger iNOS expression in brain cells. This NO-producing enzyme is normally triggered by immune responses and inflammation and is needed to fight off certain infections. But in the brain, iNOS may contribute to mitochondrial and protein damage that destroys neurons.
This group and others found iNOS in brain lesions of patients with Alzheimer's disease, but no studies had investigated whether iNOS contributed to disease progression. Nathan and colleagues now show that Alzheimer's-prone mice that lack iNOS live twice as long and develop fewer amyloid plaques than iNOS-expressing mice. Both groups of mice developed some plaques initially, but the iNOS-deficient mice were spared the rapid accumulation of plaques later in life.
The delayed effect of the iNOS deficiency was likely due to a positive feedback loop between the enzyme and the Aβ peptide, suggests Nathan. Aβ might have to accumulate before it triggers the production of iNOS. iNOS then exacerbates Aβ accumulation, perhaps in part by blocking proteasomal degradation, a pathway the cell uses to dispose of Aβ. When this loop is interrupted, disease progression is slowed. The group now plans to test iNOS inhibitors in Alzheimer's-prone mice to see if a pharmacological approach recapitulates the genetic approach.
Based on these results, Nathan suggests that iNOS inhibitors—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.