A Beneficial Link Between a Nicotine Metabolite and Alzheimer's Disease
By Jason Socrates Bardi
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 glucosea common sugar found in the bodyattaches
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, 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
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 fashionprevent 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. The article will appear in print later
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