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New way of controlling cholesterol
may help treat Alzheimer's
BOSTON - October 13, 2004 - A new approach to controlling
blood cholesterol levels that is already being investigated to prevent
cardiovascular disease also may be a potential treatment for Alzheimer's
disease. In their report in the October 14 issue of Neuron,
researchers from Massachusetts General Hospital (MGH) show that
blocking a pathway that controls the distribution of cholesterol
in cells dramatically reduces the number of amyloid plaques in the
brains of transgenic mice. Some of the treated mice were much better
at learning their way through a maze than were untreated mice.
"We found that this way of reducing cholesterol levels in the
brains of living animals both decreased amyloid deposition and improved
learning," says the study leader Dora Kovacs, PhD, director
of the Neurobiology of Disease Laboratory in the Genetics and Aging
Research Unit of MassGeneral
Institute for Neurodegenerative Disorders. "As far as we
know, this is the first study of cholesterol metabolism's impact
on amyloid levels that included cognitive testing."
Researchers have been investigating a potential relationship between
cholesterol metabolism and Alzheimer's since it was found that a
particular variant of the gene for a protein called apoE significantly
increased risk of the disease. Since the apoE protein transports
cholesterol, that discovery suggested that disruption of cholesterol
handling might cause or worsen the development of the amyloid plaques
that characterize Alzheimer's disease. In addition, some epidemiologic
studies have suggested that people taking statin drugs to control
blood cholesterol have a reduced incidence of Alzheimer's.
In 2001 Kovacs' team showed in cells that the activity of an enzyme
called ACAT, which controls whether cholesterol is stored in the
cellular membrane or in intracellular droplets, also appears to
regulate the formation of amyloid-beta, the protein fragments that
make up amyloid plaques. The current study was designed to test
that same approach in living animals.
At first, researchers tested whether the ACAT inhibitor used in
the 2001 study would affect cholesterol storage in brain cells of
mice. Because ACAT inhibitors are metabolized quickly, the researchers
used implantable pellets that release the compound in a steady manner
and found that the inhibitor significantly reduced the number of
cholesterol droplets in brain cells of normal mice.
They then implanted inhibitor pellets in mice with a human gene
that leads to amyloid plaque formation. Examination of brain tissue
after two months of treatment found that mice receiving the ACAT
inhibitor had 90 percent less plaque than did transgenic mice who
received placebo pellets. The results were even more dramatic in
female mice, who usually develop plaques earlier than males do.
Biochemical analysis of mouse brain tissue showed that the inhibitor
probably prevents amyloid-beta production, rather than reducing
its deposition.
To evaluate the effect of ACAT inhibitor treatment on the mice's
cognitive abilities, the researchers had groups of treated and untreated
mice swim through a water maze three times a day for four days.
The inhibitor did not make a difference for the male mice, which
was expected since only female mice would be expected to have enough
amyloid in their brains to reduce their ability to find the hidden
platform in the water. But those females who received the inhibitor
were markedly better at learning the maze than were females with
placebo pellets only. In fact, treated female mice learned the maze
as well or better than nontransgenic mice did.
While the particular ACAT inhibitor used in this study is not yet
appropriate for human trials, Kovacs notes, other ACAT inhibitors
are in the process of clinical testing in humans for cardiovascular
disease. Her group is now studying one that has been in Phase 3
clinical trials. "It's possible that combining these inhibitors
with statin drugs could have even more beneficial effects. If we
can duplicate what we found in this animal study with the drug that
reached Phase 3 human trials, we could cut ten years from the usual
drug development timetable," she says.
Trying to reduce amyloid deposition through cholesterol metabolism
may have a special benefit over some other strategies, Kovacs notes.
"Many other drugs in development for Alzheimer's target the
secretases" - enzymes that cut the larger amyloid precursor
protein into smaller fragments, including amyloid-beta. "Because
secretases have normal functions, secretase inhibitors have to be
tailored to selectively stop amyloid-beta production. Since they
do not affect secretases, ACAT inhibitors may have fewer side effects."
Kovacs is an assistant professor of Neurology at Harvard Medical
School.
Co-authors of the Neuron study include first authors Birgit
Hutter-Paier, PhD, of JSW Research in Graz, Austria, and Henri Huttunen,
PhD, of MGH; Luigi Puglielli, MD, PhD, Doo Yeon Kim, PhD, Robert
Moir, PhD, Sarah Domnitz, and Matthow Frosch, MD, PhD, of MGH; and
Alexander Hofmeister, and Manfred Windisch, PhD, of JSW Research.
The study was supported by grants from the Institute for the Study
of Aging, the National Institute for Neurologic Disease and Stroke,
and the Alzheimer's Association.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $400 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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