Oxidative Stress Appears in Brain Cells Before Amyloid
into the causes of Alzheimer's Disease shows that amyloid
plaques develop while the illness is taking over the
brain but still not clinically evident. Accordingly,
the most common scientific belief holds that those plaques
contribute to or cause the oxidative damage and inflammation
that occur and, ultimately, destroy brain cells.
Now, a mouse-model study at the University of Pennsylvania
School of Medicine has demonstrated that oxidative damage
precedes the plaques -- a reversal of existing theory
that opens new paths of inquiry in combatting an illness
that afflicts one out of every 10 persons over the age
"Alzheimer's Disease is a very complex disease
that does not appear to have a single cause, but our
research indicates that oxidative stress is probably
a primary event in the course of the illness,"
said Domenico Pratico, MD, of the Department of Pharmacology
in Penn's School of Medicine and a member of Penn's
Center for Experimental Therapeutics. He is corresponding
author of the study, which will be published Friday
in the June 15 issue of The Journal of Neuroscience.
The primary target of Alzheimer's Disease (AD) is the
hippocampus, followed by the frontal and temporal lobes
of the brain, all of which can lose between 30 and 40
percent of their neurons as the disease progresses.
Most scientists investigating the illness base their
work on one of two main theories.
The first holds that as amyloid plaques develop, they
cause an inflammation in microglia cells that backfires,
stimulating the production of cytokines that attack
and damage neurons.
The second theory is based on the action of free radicals.
About 95 percent of the brain is made up of fatty lipids
that, when attacked by free radicals, undergo peroxidation
(oxidative damage.) That leads, in turn, to cell malfunction
and eventual cell death. It is known that amyloid beta
protein can produce free radicals on its own, as well
as stimulate other cells to do the same. Many scientists
believe that a build-up of amyloid plaques causes a
parallel increase in free radicals, which eventually
reach the point where they overwhelm the brain's power
to destroy them -- resulting in what is called oxidative
At the core of both theories is the belief that amyloid
plaques constitute an initiating factor in the onset
of Alzheimer's Disease. Pratico and his colleagues decided
to establish whether that is true. They discovered that
free radicals show up even earlier on the scene.
The scientists studied mice that had been engineered
to produce amyloid-beta plaque at a rapid rate.
The Penn researchers studied the brains of the engineered
animals and a control group at six developmental milestones:
four weeks, four months, eight months, 12 months, 15
months, and 18 months.
"At seven months, there is 25 percent more oxidative
damage in the AD mice than is present in normal mice,
and this differential keeps increasing until it is 100
percent higher at 10 or 11 months," Pratico said.
"At 12 months, oxidative damage is 200 percent
higher" than in the normal mice.
In the engineered mice, the plaques were still undetectable
at eight months.
"This opens a lot of interesting hypotheses for
therapeutics," Pratico said. "If you reduce
oxidative stress in these animals very early, when they
are very young, can you prevent the formation of amyloid?
And by how much? We know Vitamin E, which is an anti-oxidant,
can temporarily slow the progression of AD for some
patients. What we don't yet know is what will happen
if we suppress, reduce or delay oxidative stress over
the long run."
Others who collaborated in the study were Kunihiro Uryu,
PhD, John Q, Trojanowski, MD, PhD, and Virginia M.-Y
Lee, PhD, of Penn's Department of Pathology and Laboratory
Medicine. Trojanowski and Lee are codirectors of the
Center for Neurodegenerative Disease Research, and Uryu
is a member of the center's staff.
The research was funded by the American Heart Association,
the National Institute on Aging, the National Institutes
of Health, and the Oxford Foundation.
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