On Press:
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 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, 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. The article will appear
in print later this year.
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