Alzheimer's Disease Symptoms
Reversed in Mice
A cancer drug given to mice eliminates brain-damaging
to improved cognition within days, but will it work in humans?
Stix | Thursday, February 9, 2012 | 6
13-year-old skin cancer drug rapidly alleviates molecular signs ofAlzheimer's
disease and improves brain function, according to the results of
a new mouse study being hailed as extremely promising. Early-stage human
clinical trials could begin within months.
In the study,
February 9 by Science, researchers
from Case Western Reserve University in Cleveland and colleagues used mice
genetically engineered to exhibit some of the symptoms of Alzheimer's. Most
notably, the mice produced amyloid
beta peptides—toxic protein fragments that gum up neurons and
lead to cell death—and showed signs of forgetfulness.
Amyloid beta (red
peptides clear from the brain of an Alzheimer's mouse after three days of
treatment with a cancer drug (right
The Case Western
team, led by Gary
Landreth, decided to try the drug bexarotene
(Targretin), approved in 1999 for cutaneous T cell lymphomas. The
team chose this drug because of its long experience working with proteins in
the nucleus of brain cells that can induce biochemical processes that affect
his colleagues fed bexarotene to the demented mice, and with just a single
dose it lowered the most toxic form of the amyloid beta peptide by 25
percent within six hours, an effect that lasted for up to three days. Mice
that were cognitively impaired by the amyloid buildup resumed normal
behaviors after 72 hours: They began to crinkle toilet paper placed nearby
to make nests, a skill lost as amyloid increased in their brains.
successfully reversed all of the known pathological features and behavioral
deficits found in mouse models of Alzheimer's disease," Landreth says.
"Never before has anyone observed clearance of amyloid plaques with such
speed in mouse models."
Alzheimer's researchers hail the work. "I think this is extremely
promising," says Samuel Gandy, a professor of neurology and psychiatry at
Mount Sinai School of Medicine and associate director of the hospital's
Alzheimer's Disease Research Center. "One of the drugs that has been on our
wish list for 25 years is a drug that would clear existing amyloid
paper is impressive," adds Kenneth Kosik, a neuroscientist at the University
of California, Santa Barbara. "The effects in mice, including some
restoration of cognitive abilities, are dramatic."
In a field littered with drug failures, the study offers hope that the
strategy of clearing the brain of the toxic peptide can work. Bexarotene
does not do so directly, however; instead, it activates retinoid receptors
on brain cells that increase production of a fat-protein complex,
apolipoprotein E, that helps rid excess amyloid in the fluid-filled space
between neurons. It also appears to enhance another cleanup process, called
functions differently than an amyloid-clearance approach using monoclonal
antibodies, which are further down the drug development pipeline. These
antibodies bind directly to amyloid and then remove it, but they have
sometimes caused fluid to fill brain tissue. Bexarotene may be less likely
to cause such swelling. "I think the fact that we're inducing a natural
process by turning on these receptors doesn't lend itself to water on the
brain," says Paige Cramer, Landreth's graduate student who performed much of
the research. Unlike bexarotene, which is taken orally, monoclonals are more
troublesome to administer, because they must be delivered intravenously, and
if they receive U.S. Food and Drug Administration approval, they would
likely be significantly more expensive.
The study also
provides the most compelling evidence to date of how the biggest risk factor
for Alzheimer's later in life—having the so-called Apolipoprotein E (APOE)
gene, identified in the early 1990s—might yield a strategy for new
therapies. The gene for apolipoprotein E comes in three versions, one of
which, the e4 variant, confers a significantly higher risk of getting
the disease—a roughly 60 percent chance at age 80 for those who carry a copy
from both their mother and father, as against a less than 10 percent overall
risk at that age in the general population. The gene variant, known
informally as the Alzheimer's gene, is common: about 20 percent of the U.S.
population has at least one copy. The e4 carriers may be vulnerable
to Alzheimer's because they have a diminished ability to clear amyloid, a
hypothesis that seems to be reinforced by this Case Western study.
Jumping the gun?
That idea, though, is not universally endorsed. Some experiments have shown
that the e4 version may also impair the brain in other ways, perhaps
by bollixing the biochemical functioning at the synapses, the connection
points between neurons, or by producing toxic fragments of the lipoprotein
that damage neurons. If so, increasing the production of this form of
apolipoprotein E could actually worsen the pathology of the disease and
would complicate greatly bexarotene's development.
hurdle does not dissuade one researcher experienced in Alzheimer's clinical
trials. "I am not particularly concerned" about potential toxic effects of
extra e4 production, says Paul Aisen of the University of California,
San Diego, who heads the Alzheimer's Disease Cooperative Study, which
organizes clinical trials for drugs to combat the illness. "If it
significantly enhances amyloid clearance and reduces the burden of brain
amyloid, there is a good chance it will succeed." David Holtzman, a
prominent Alzheimer's researcher from Washington University in Saint Louis,
echoes the sentiment about bexarotene's prospects: "I do think it is
promising to go into humans."
Cramer certainly think so. They have formed a company called ReXceptor
Therapeutics that intends to begin a preliminary trial in humans in the next
few months to determine whether the drug crosses the blood–brain barrier and
clears amyloid, as it does in mice. If those processes occur, clinical
trials on the drug's effectiveness in humans could begin even this year, and
they would probably last from 18 months to three years. The drug loses
patent protection for cancer this year, but Case Western has filed for
patents for its use in Alzheimer's.
Despite their optimism, scientists say it's important not to overplay the
progress. After all, drugs that work in mice do not necessarily help humans.
Moreover, the genetically engineered version of mice used in this study do
not recapitulate every aspect of the human disease. For instance, the mice
do not experience the effects of dying neurons (despite having impaired
cognition), and they do not go on to develop a hallmark characteristic of a
later disease stage in humans—namely, the accretion of so-called tau
proteins that seem to abet the killing of nerve cells. "Transgenic mouse
experiments have not reliably predicted therapeutic effects in humans,"
Aisen says, "so caution is essential until human studies confirm target
engagement," that is, the removal of amyloid plaques.
bexarotene does not come without risk: it raises levels of triglycerides,
blood fats implicated in cardiovascular disease and diabetes. The Case
Western mouse work suggests that Alzheimer's patients may benefit with doses
lower than those ingested for cancer treatment, which might produce less of
an effect on fat levels. Whether the drug remains effective over time is
another question. The levels of amyloid plaques—although not the apparently
more toxic soluble form of the peptide—rose after 90 days, a suggestion that
the drug may be metabolized differently after ingestion over long periods.
enthusiasm generated for a mouse study stems from the desperation for new
ideas as the number of Alzheimer's cases, now at 5.4 million in the U.S., is
expected to more than double by the year 2050 as the nation's demographic
profile continues to gray. A better understanding of the disease process—the
knowledge that pathology begins 10 or 20 years before the first symptom—has
shifted focus toward earlier drug trials. New technologies that combine
brain imaging and spinal fluid tests might identify at-risk patients and
test new drugs. A relatively inexpensive drug that can be ingested orally,
such as bexarotene, could then be prescribed to at-risk but symptom-free
patients, who would take them over the course of their lifetimes, like a
moves forward with its clinical trial plans, it will inevitably have to
contend with the demands of the families of Alzheimer's patients. Landreth
emphasizes that calling your physician after reading an article like this
one is a bad idea. "Don't try this at home," he cautions, "because we don't
know we what dose to give, we don't know how frequently to give it, and
there are a few nuances to its administration. So one shouldn't be
prescribing it off-label." It is also unclear whether a drug like bexarotene
would work at a middle or advanced stage of the disease, when
neurodegenerative processes have already set in.
genesis as an Alzheimer's treatment comes as an outgrowth of Landreth's
long-time fundamental work on cell receptors. If it succeeds, it will
demonstrate that new ideas for treating this seemingly intractable disease
may come from beyond the sometimes narrowly focused strategies of large