Dora M. Kovacs talks with
ScienceWatch.com and answers a few questions about
this month's Fast Moving Front in the field of Neuroscience
Alzheimer's disease: the cholesterol
Authors: Puglielli, L;Tanzi,
Journal: NAT NEUROSCI, 6 (4): 345-351 APR 2003
Addresses: Harvard Univ, Sch Med, Neurobiol Dis Lab,
CAGN,Massachusetts Gen Hosp, Charlestown, MA 02129
Harvard Univ, Sch Med, Neurobiol Dis Lab,
CAGN,Massachusetts Gen Hosp, Charlestown, MA 02129
Harvard Univ, Sch Med, Genet & Aging Res Unit,
CAGN,Massachusetts Gen Hosp, Charlestown, MA 02129 USA.
Why do you think your paper is highly
Our article addresses the connection between two important health issues,
cholesterol and Alzheimer's disease (AD). Given that drugs currently on the
market can reduce blood cholesterol levels, the question is whether these
same drugs can also alleviate symptoms of AD. Therefore, interest in this
connection is high from researchers around the world.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
This review paper outlines our current understanding of the role of
cellular cholesterol in AD. Cellular cholesterol levels and distribution do
not always correlate with blood cholesterol. However, the toxic molecule in
AD called amyloid-ß (Aß) peptide is generated from cells,
necessitating studies on cellular cholesterol. We have also summarized
potential therapeutic strategies based on modulating cholesterol in
patients affected by the disease. We have placed particular effort on
fairly representing all aspects of this connection, including cellular,
animal, and clinical studies.
Would you summarize the significance of your paper
in layman's terms?
Genetic and epidemiological data support a role for altered cholesterol
metabolism in the pathogenesis of AD. In particular, studies of both animal
and cellular models of AD show that cholesterol within single cells
(intracellular) regulates the generation of the toxic Aß ?peptide. In
animal models, hypercholesterolemia induced by high-cholesterol diets
increased deposition of Aß in brains of rabbits and transgenic mouse
models of AD. Pharmacological agents such as statins and ACAT inhibitors,
which induce changes in cellular levels and distribution of cholesterol,
have repeatedly been shown to modulate Aß production.
"Therapies already developed for
atherosclerosis and cardiovascular disease
are being considered for Alzheimer’s
Statins reduce Aß production in cells and in most animal models of
AD. Mechanistically, statins not only reduce cholesterol, but also affect
other metabolic pathways. Unfortunately, so far statins have failed to
consistently improve symptoms of AD in clinical trials.
Our own interest lies in another promising cholesterol pathway, mediated by
acyl-coenzyme A: cholesterol acyltransferase (ACAT). ACAT inhibition has
long been studied as a potential antiatherosclerotic strategy, resulting in
both reduced intestinal cholesterol absorption and foam cell formation. We
have first presented genetic, metabolic, and pharmacological evidence that
ACAT inhibition dramatically reduces Aß generation. Later, we
confirmed this in animal models of AD.
Therefore, the significance of studying the role of cholesterol in AD is
three-fold. First, statins and/or ACAT inhibitors represent potential
strategies for the prevention and/or treatment of the disease. Second,
mechanistic studies will lead to the understanding of novel pathways for
the regulation of Aß ?generation. Third, these novel pathways may in
turn lead to novel therapeutic strategies for reducing Aß production
in AD patients.
How did you become involved in this research and
were any particular problems encountered along the way?
More than 10 years ago, we had noticed that a particular cell line lacking
ACAT failed to generate the toxic Aß ?peptide. We confirmed this by
inhibiting ACAT in different ways in cell-based models of AD and in primary
neurons. We showed that two existing ACAT inhibitors also inhibited
Aß production by up to 50%. Excited by these results, we examined the
effect of ACAT inhibitors in transgenic mouse models of AD. In particular,
in one model we found that two months of treatment with an ACAT inhibitor
decreased brain amyloid plaque load by 88-99% and insoluble Aß levels
These results are highly encouraging for the potential use of ACAT
inhibitors in AD patients. However, ACAT inhibitors are currently not
marketed for the prevention of high blood cholesterol or atherosclerosis.
More research is needed to develop safe and effective inhibitors for human
Where do you see your research leading in the
Therapies already developed for atherosclerosis and cardiovascular disease
are being considered for AD. Clinical trials with statins are ongoing. As
the mechanism of action of ACAT inhibitors is not well-characterized, more
studies are needed to determine how exactly ACAT inhibition reduces
generation of the toxic Aß peptide.
More recently, we've studied an ACAT inhibitor which has previously been
tested in clinical trials for prevention of atherosclerosis. As expected,
this inhibitor also improved AD-like pathology in the brains of transgenic
mice. Most importantly, it was also effective in an older animal group
where the mice had already developed significant pathology before the
treatment. This experiment was similar to treating AD patients, as in this
case the mice have recovered from already existing amyloid pathology. Our
studies using older animals offer the strongest hope that ACAT inhibition
may be considered for the treatment and prevention of AD.
Do you foresee any social or political implications
for your research?
Our finding that ACAT inhibition reduces Aß generation in
vitro and in vivo suggests that ACAT inhibitors, currently
under development for the treatment of cardiovascular disease, may also be
effective in the treatment of amyloid pathology in AD patients. We hope
that our findings will encourage the development of new ACAT inhibitors and
clinical trials with these new compounds against AD.
Dora M. Kovacs, Ph.D.
Associate Professor of Neurology
Neurobiology of Disease Laboratory
Genetics and Aging Research Unit, MIND
Massachusetts General Hospital/Harvard Medical School
Charlestown, MA, USA