La Jolla, CA. June 16, 2003 — Two scientists at The Scripps Research Institute (TSRI) have discovered that a chemical called nornicotine modifies proteins that misfold and form the fibril plaques that are abundant in the brains of patients with Alzheimer's disease. Nornicotine is naturally present in tobacco and is also produced as a major metabolite of nicotine.
In an article to be published in the Proceedings of the National Academy of Sciences, the researchers demonstrate that nornicotine combined with glucose—a common sugar found in the body—attaches itself "covalently" (permanently) to amino acids on the surface of amyloid beta protein and prevents these proteins from misfolding and forming fibrils.
"This modification leads to decreased aggregation of the peptide," says TSRI graduate student Tobin Dickerson. "In essence, this process physically blocks [the formation of the fibrils]."
Whether or not this effect might ameliorate Alzheimer's disease is not known. Fibrils of aggregated amyloid beta protein are present in the brains of Alzheimer's patients, and the aggregation of amyloid beta protein is an accepted primary pathological marker for Alzheimer's. But the exact cause of Alzheimer's disease is still not clear. These fibrils may be causing the disease or they may be just a marker of the disease.
"Amyloid beta proteins are thought to be a major player in Alzheimer's disease," says Professor Kim Janda, Ph.D., who holds the Ely R. Callaway, Jr. Chair in Chemistry at TSRI and is an investigator in The Skaggs Institute for Chemical Biology at TSRI. "Nornicotine seems to prevent their aggregation and, thus, could potentially impact the onset of Alzheimer's disease."
In any case, warns Janda, these conclusions do not necessarily mean that smoking prevents Alzheimer's disease, and this research gives no indication that smoking is beneficial to your general health. "There are a vast number of toxic components in tobacco smoke. We're certainly not advocating smoking," says Janda.
Although nornicotine appears to have a positive effect, it is not likely that it would make a good therapeutic. Nornicotine is highly toxic and addictive.
Nevertheless, the research is promising because it demonstrates how one small molecule can cause a chemical interaction that may alter a mechanism important in Alzheimer's disease. This could lead to the development of small molecules similar to nornicotine that are not toxic but could behave in a similar fashion—prevent the aggregation of amyloid beta protein and perhaps treat Alzheimer's disease.
This work also highlights the need for further study of the consequences of exposing the human body to nicotine metabolites, like nornicotine.
The article, "Glycation of the amyloid beta-protein by a nicotine metabolite: A potentially fortuitous chemical dynamic between smoking and Alzheimer's disease" was authored by Tobin J. Dickerson and Kim D. Janda and appears in the online edition of the journal Proceedings of the National Academy of Sciences the week of 6/16/2003 to 6/20/2003 at http//www.pnas.org/cgi/doi/10.1073/pnas.1332847100 . The article will appear in print later this year.
This work was supported by The National Institute on Drug Abuse and by The Skaggs Institute for Research.
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