Gregory M Cole talks with
ScienceWatch.com and answers a few questions about
this month's Fast Moving Fronts paper in the field of Biology
& Biochemistry.
Article: Curcumin inhibits formation of amyloid beta
oligomers and fibrils, binds plaques, and reduces amyloid in
vivo Article: Curcumin inhibits formation of amyloid beta
oligomers and fibrils, binds plaques, and reduces amyloid in
vivo
Authors: Yang, FS;Lim, GP;Begum, AN;Ubeda, OJ;Simmons,
MR;Ambegaokar, SS;Chen, PP;Kayed, R;Glabe, CG;Frautschy,
SA;Cole, GM
Journal: J BIOL CHEM, 280 (7): 5892-5901 FEB 18 2005
Addresses: Univ Calif Los Angeles, Dept Med, Greater Los
Angeles VA Healthcare Syst CRECC11E, 16111 Plummer St,
Sepulveda, CA 91343 USA.
Univ Calif Los Angeles, Dept Med, Greater Los Angeles VA
Healthcare Syst CRECC11E, Sepulveda, CA 91343
USA.
(addresses have been truncated.)
Why do you think your paper is highly
cited?
Our paper shows that a small natural molecule, with established preclinical
(National Toxicology Program) and clinical trial safety, directly binds and
inhibits amyloid beta oligomer formation and toxicity in vitro and
enters the brain and binds abeta in vivo where it dramatically
reduces amyloid beta deposits even with late intervention in vivo.
Because the structure and binding is common for multiple beta sheet
proteins, the paper is relevant to multiple protein aggregate disorders
(Alzheimer's disease [AD], tau pathologies,
Parkinson's disease [PD], Huntington's disease [HD], CAG repeat
disorders, etc).
Does it describe a new discovery, methodology, or
synthesis of knowledge?
In 2001, we had shown that curcumin reduced amyloid accumulation with early
intervention in an APP Tg model, but we had no mechanism. We presented data
at meetings over the next several years showing that, like the well-studied
amyloid beta vaccine/antibodies, curcumin binds to abeta aggregates and
improves their clearance by microglia.
This paper does not include the microglia data, but shows the data
demonstrating direct anti-oligomer drug activity and plaque-binding
mechanisms that synthesize knowledge that can be generalized for multiple
neurodegenerative diseases. It combines multiple useful in vitro
and in vivo methods to show mechanism and in vivo utility
of an agent with anti-protein aggregate activity.
"If curcumin succeeds in human trials for Alzheimer's
or any of the many other diseases of aging it shows promise
for, it will become a major player in our prevention
efforts. "
A key point of significance in this paper is that it is one of the only
papers to show that, like a passive antibody, a small molecule can
dramatically reduce aggregate accumulation after the plaque formation has
plateaued. This is very important because amyloid formation occurs decades
before clinical symptoms and plateaus before disease onset.
Our 2005 paper was followed by a paper from Brian Bacskai of the Harvard
Medical School, who used multiphoton in vivo imaging to confirm
that injected curcumin labeled plaques and also to prove that pre-existing
plaques were actually cleared by curcumin treatment—similar to the
antibody approaches now being used in trials.
Would you summarize the significance of your paper
in layman's terms?
Neurodegenerative diseases are often caused by aggregated proteins with
common structural features found in difficult-to-degrade proteins that can
form long fibers. The one we are familiar with is found in hair, which is
so difficult to degrade that it can last long after the person or animal
producing it has died.
This type of protein structure is difficult for an animal or bacteria to
digest—think of cats and fur balls. This type of protein structure is
found in many age-related dementing diseases like AD but also in PD,
"mad cow," and other less common conditions.
Our paper shows that a small natural compound from curry spice which is
safe to use in humans can treat these protein aggregates by binding
directly to them in the laboratory and it also shows that it can enter the
brains of living aged animals where it finds and binds the toxic protein
aggregates that attack brain cells to cause a disease such as AD.
Our paper shows that curcumin can dramatically reduce the accumulation of
this type of protein aggregate—even when intervention is late and
after the aggregates have built up. Because these aggregates build up long
before clinical symptoms, late intervention with a safe treatment offers
hope for a new way to prevent or treat AD and related diseases.
How did you become involved in this research and
were any particular problems encountered along the way?
We have long sought to find a way to prevent or treat the diseases of aging
because everyone is at risk for them and we have no cures. The first
problem for AD has been to find animal models where drugs can be tested, so
we worked with
Professor Karen Hsiao Ashe of the Department of
Neurology and Neuroscience at the University of Minnesota to develop a
mouse model that academics could use (1996).
We sought to first test non-steroidal anti-inflammatory drug (NSAID)
treatments because more than 20 epidemiological studies have shown NSAID
users have less AD. In the year 2000, we reported that the most widely used
NSAID (ibuprofen) delayed pathology in that model, but elderly people are
at risk for GI bleeds and other problems from chronic NSAID use.
So we looked for safer NSAIDs and found that curcumin was an alternative
used in traditional Indian and Chinese medicines. It also has antioxidant
properties like vitamin E which has shown some promise, so we tested
curcumin along with 12 other candidates against toxic beta amyloid
aggregates in a rat model.
Curcumin was the best of our 12 candidates, so we moved it into the mouse
model for chronic treatment. Curcumin worked well with early intervention,
which we published in 2001.
Another NSAID (naproxen) actually looks like it might have reduced AD in a
big prevention trial but that trial had to be stopped because of
side-effect worries. So, this 2005 study showing curcumin works well
against oligomers and plaques even with late intervention is promising.
Where do you see your research leading in the
future?
Curcumin has a problem with poor bioavailabilty in humans, so it hasn't
worked as well in human clinical trials as it does in preclinical tests,
but we have now solved this problem and it is going back into the clinic.
Do you foresee any social or political
implications for your research?
If curcumin succeeds in human trials for AD or any of the many other
diseases of aging for which it shows promise, it will become a major player
in our prevention efforts. Many researchers already have and will continue
to contribute to this effort because curcumin may be turn out to be a
wonder drug—like aspirin!
Greg M. Cole, Ph.D.
Associate Director, Basic Research
Geriatric Research, Education and Clinical Center (GRECC)
Associate Director
Mary Easton Alzheimer Disease Center
University of California at Los Angeles
Los Angeles, CA, USA
Professor, Departments of Medicine & Neurology
University of California at Los Angeles
Los Angeles, CA, USA Web