PDF format for best printing results. Full
text also follows:
Two
new research findings suggest that boosting normal, protective processes
in the brain might help degrade or prevent damaging protein plaques
associated with Alzheimer's disease (AD). In one publication, researchers
at The Salk Institute and colleagues at other institutions found that
gene transfer of the enzyme neprilysin may help clear a protein that
forms amyloid plaques in humans. The experiments -- in mice -- are
an important step in the development of an alternative approach to
controlling AD and suggest closer study of the potential for neprilysin
therapy.
The
findings, by Fred H. Gage, Robert A. Marr, and Inder M. Verma at The
Salk Institute for Biological Studies, Eliezer Masliah at the University
of California San Diego and Atish Mukherjee and Louis B. Hersh at
the University of Kentucky, Lexington, are reported in the latest
issue of The Journal of Neuroscience.*
The
Gage report comes on the heels of another study, reported March 3,
2003, in the online version of Nature
Medicine, by Jens Husemann, Columbia University, New York,
Tony Wyss-Coray, Veterans Affairs Palo Alto Health Care System and
Stanford University in California, and colleagues. Husemann's group
found that certain cells in the brain, called astrocytes, can degrade
the beta amyloid peptide in cell cultures. While not yet tested in
an animal model, the study's finding that astrocytes can be effectively
mobilized at the cellular level suggests yet another possible target
for potential therapies for AD.
"In
recent years, we have been looking at ways to battle amyloid,"
says Brad Wise, Program Director, Fundamental Neuroscience, the National
Institute on Aging's (NIA) Neuroscience and Neuropsychology of Aging
Program. "Most studies have focused on blocking the production
of proteins that form AD plaques. Both of these studies suggest how
we might clear amyloid even if it does build up in the brain. These
are very new ways of addressing the problem."
The
Gage research was funded by the NIA, part of the National Institutes
of Health, U.S. Department of Health and Human Services. Funding was
also provided by the Alzheimer's Association, the Canadian Institutes
of Health Research, and other funds and foundations. The Husemann
study was funded by the NIA and the Alzheimer's Association.
Scientists
have known for many years that amyloid plaques in the brain are a
hallmark feature of AD in humans. Studies on the etiology of the disease
have shown that the plaques are formed when the larger amyloid precursor
protein (APP) is broken up, resulting in the formation of beta amyloid
protein fragments, or abeta peptides, that clump together to form
insoluble amyloid plaques in certain areas of the brain with AD. It
has been hypothesized that one approach to preventing AD or delaying
its clinical symptoms might be to interfere with the production of
beta amyloid or, more recently, to degrade beta amyloid or its plaques.
Previous
research has shown that neprilysin is reduced in areas vulnerable
to plaque formation and that mice without the neprilysin gene have
increased levels of beta amyloid in the brain. Test tube studies have
also shown that neprilysin could help stop the production of beta
amyloid.
The
current experiments reported by Gage and colleagues represent the
first demonstration that increased levels of neprilysin decrease the
deposition of amyloid in an animal model. In this study, the team
injected gene vectors carrying human neprilysin into the amyloid-containing
brains of transgenic mice. The gene transfer was concentrated in two
areas of the brain, the hippocampus and the frontal cortex, both areas
where plaque formation occurs in humans.
At the
end of the treatment, the researchers reported, introduction of the
neprilysin appeared to increase degradation or reduce the growth of
already existing plaques. Plaques found in areas strongly "expressing"
neprilysin, near the injection sites, were found to be smaller and
more compact than in other regions of the brains. In some cases, what
the researchers call plaque "load" was reduced to less than
half that found in comparable, untreated areas. There was also evidence
that neurodegeneration, neuronal cell damage, was reduced after the
neprilysin gene transfer.
"If
we find a way to shift the balance between amyloid production, clearance,
and degradation, I believe we can find a way to interfere with the
processes involved in Alzheimer's disease," says Gage. "Further
study will help define the role of neprilysin in regulating amyloid
and possibly treating or preventing AD."
Astrocytes,
a type of cell which supports, nourishes, and protects neurons in
the brain, are found around and are in contact with AD plaques. Husemann
and colleages theorized that astrocytes near the AD plaques may not
only immobilize or bind to abeta peptides in the brain, but might
also degrade the abeta, which they found to be the case with adult
mouse astrocytes.
The
team then set out to see if adult astrocytes could also "process"
abeta deposits from brain tissue. They incubated adult astrocytes
on brain sections of transgenic mice making human APP. After 24 hours
incubation with astrocytes, the area of the hippocampus occupied by
abeta was reduced by 40 percent, Husemann and colleagues found. "The
findings raise the intriguing possibility that defects in astrocyte
cell clearance of abeta may contribute to the formation of AD plaques,"
notes Husemann. "Harnessing the protective function of these
cells may be a strategy for AD prevention and treatment."
The
NIA leads the Federal effort to support and conduct basic, clinical,
and social and behavioral studies on aging and on AD. It supports
the Alzheimer's Disease Education and Referral (ADEAR) Center, which
provides information on AD research.
ADEAR's
website can be viewed at http://www.alzheimers.org,
where several publications may be found on the causes and course of
AD, including the new publication Alzheimer's Disease: Unraveling
the Mystery at http://www.alzheimers.org/unraveling/index.htm
and the detailed Progress Report 2000 at http://www.alzheimers.org/prog00.htm,
which describes the broad Federal research program on AD.
The
public and health professionals may also call ADEAR toll free, 1-800-438-4380.
Press releases, fact sheets, and other materials about aging and aging
research can be viewed at the NIA's general information Web site,
http://www.nia.nih.gov.
*The
Journal of Neuroscience findings were publicly released March
25, 2003, at 5 p.m. Eastern Time, appearing in the journal issue dated
March 15, 2003.
###