Ganoderma Guide

Key brain antioxidant linked to Alzheimer's and Parkinson's


Key brain antioxidant linked to Alzheimer's and
Parkinson's
December 15, 2005
EAAC1 protein is the main transporter of
cysteine into neurons, providing vital antioxidant protection
A study conducted at the San Francisco VA Medical Center has
identified a protein found in both mice and
humans that appears to play a key role in protecting neurons from
oxidative stress, a toxic process linked to neurodegenerative
illnesses including Alzheimer's and Parkinson's diseases.


The study, led by Raymond Swanson, MD, chief of neurology and
rehabilitation services at SFVAMC, identified the
protein - known as EAAC1 in mice
and as EAAT3 in humans - as the main mechanism through which the
amino acid cysteine is transported into neurons. Cysteine is an
essential component of glutathione, which Swanson terms "the most
important antioxidant in the brain."
It had been thought previously that the main function of the
protein was to remove excess glutamate, a neurotransmitter, from
brain cells.
"It's known that neurons don't take up cysteine directly, and
it's never been clear exactly how it gets there," says Swanson, who
is also professor and vice chair of neurology at the University of
California, San Francisco.

"This study provides the first evidence
that EAAC1 is the mechanism by which cysteine gets into neurons -
and that transporting cysteine is probably its chief function."
Study findings are currently available in the Advance Online
Publication section of Nature Neuroscience.
Antioxidants such as glutathione provide protection from
oxidative stress, which kills cells through the "uncontrolled
reaction of lipids in the cells with oxygen-basically, burning them
out," says Swanson. Since the brain uses a lot of oxygen and is
"chock full of lipids," it is particularly vulnerable to oxidative
stress, he notes.


In the first part of the study, Swanson and his co-authors
observed a colony of mice deficient in the gene responsible for the
production of EAAC1 and compared their behavior with that of a
colony of normal, or "wild type," mice. They noticed that around
the age of 11 months - old age for a mouse - the gene-deficient
mice began to act listlessly, not groom themselves properly, and
exhibit other signs of senility. In contrast, the wild type mice
"looked and acted totally normal," according to Swanson.
Then, in postmortem examination, the researchers found that the
brains of the EACC1-deficient mice had abnormally enlarged
ventricles - openings within the brain that provide a path for
cerebrospinal fluid - while the ventricles of the wild type mice
were normal.

Enlarged ventricles "also occur in Alzheimer's
patients," Swanson notes.
In addition, it was found that the EAAC1-deficient brains had
fewer neurons in the hippocampus, and that all neurons in the
hippocampus and cortex showed evidence of oxidative stress, unlike
in the wild type mice.
The researchers then compared brain slices from younger mice in
both groups. They found that it took ten
times less hydrogen peroxide - a
powerful oxidant - to kill slices from the EAAC1-deficient mice
than it took to kill slices from the normal mice.

This
demonstrated that brains of mice unable to produce EAAC1 were
ten times as vulnerable to oxidative stress as mice with the
ability to produce EAAC1.
The researchers also found that the neurons of the
EAAC1-deficient mice contained lower levels of the antioxidant
glutathione compared to those of the normal mice.
Taken together, these results
"support the idea that oxidative
stress contributes to aging" in the brain, a well-known concept
that Swanson calls "appealing," but difficult to prove or
disprove. "This certainly adds credence to the idea," he
says.


In the final part of the study, Swanson and his team
investigated whether oxidative stress in EAAC1-deficient mice might
be reversible.
For several days, a group of gene-deficient mice were fed
N-acetylcysteine, an oral form of cysteine that is readily taken up
by neurons. When their neuron slices were compared with slices from
untreated gene-deficient mice, it was found that N-acetylcysteine
"had completely corrected the biochemical defect" in their neurons,
recounts Swanson. "Their glutathione levels were normal, their
ability to withstand hydrogen peroxide toxicity was normal, and the
oxidants we saw in the neurons in response to oxidative challenges
were normal.

"
Based on the results of the current study, Swanson and his group
are working to determine whether EAAC1 expression is altered in
neurodegenerative illnesses such as Alzheimer's and Parkinson's
diseases. Should this prove to be the case, says Swanson, then
manipulation of EAAC1 levels "might provide a novel approach" to
the treatment of these diseases in the future.
University of California-San Francisco





.