into how iron, copper, zinc and other metals work in the brain may help
unlock some of the secrets of degenerative diseases like Alzheimer's
and copper appear to accumulate beyond normal levels in the brains of
people with these diseases, and a new, Australian study published
Sunday shows reducing excess iron in the brain can alleviate
Alzheimer's-like symptoms—at least in mice.
genetic mutation related to regulating iron is linked to ALS, or Lou
Gehrig's disease. Zinc, on the other hand, appears to impair memory if
its levels get too low or if it gets into a brain region where it
doesn't belong, as it can with traumatic brain injury.
into the complicated, invisible roles these metals play in brain
diseases has lagged behind study of the more-visible proteins that are
damaged or clump together in the brains of Alzheimer's and Parkinson's
sufferers. But better understanding metals' role in the brain could
help shed light on a range of medical conditions and might offer a new
route for developing treatments, scientists say.
field is coming around to the idea of the cause of Alzheimer's being
multifactorial," and disturbed metal regulation could be one of those
factors, says Ralph Nixon, chairman of the Alzheimer Association's
medical and scientific advisory council and director of the Silberstein
Alzheimer's Institute at New York University.
metal ions—charged particles of the elements—serve
several essential functions in the body, including facilitating
chemical reactions to generate energy and preserving the structure of
proteins. Strict checks and balances in a healthy body keep metal
levels within a tight range.
biological changes that come with disease and aging—as
opposed to poisoning from outside sources like food, supplements or
metal pans—can knock levels of these metals out of whack in
for instance, is a "double-edged sword" because it interacts with
oxygen to help the body generate energy, but also can produce free
radicals, highly reactive molecules that can cause cell damage, says
James Connor, professor and vice chairman of neurosurgery at Penn State
University in Hershey.
body has too little iron, such as with anemia, the body doesn't
generate enough energy to sustain important functions. But an
overabundance of iron accumulated in the brain is toxic. Significantly
higher accumulations of metal have been observed in the brains of
people with Parkinson's and Alzheimer's disease than in healthy people
of the same age, says Ashley Bush, a professor of pathology at the
University of Melbourne.
study, conducted by Dr. Bush and colleagues and published in the
journal Nature Medicine, examined the amount of iron in the brains of
mice that were bred unable to produce the tau protein, which helps
stabilize the structure of neurons. Tau damage is associated with
Alzheimer's and Parkinson's.
mice aged, they suffered symptoms similar to people with both diseases,
including impaired short-term memory, and also exhibited an
accumulation of iron in their brains. When the researchers gave them a
drug removing excess iron, the symptoms reversed. This means normally
functioning tau is necessary for removing iron in the brain, Dr. Bush
says. The finding bolsters previous research showing that bringing down
iron may be a path to new treatments.
accumulation of iron in neurons seems to be a final end-stage event in
neurodegeneration, whether it be Alzheimer's or Parkinson's, [or] any
[condition] related to tau abnormalities," says Dr. Bush, who is also a
fellow at the university's Mental Health Research Institute.
proteins affected in Alzheimer's also play a role in metal regulation.
The amyloid precursor protein is important in helping export iron from
the brain, according to work published in the journal Cell in 2010.
Presenilin, another protein that aids in metal uptake, is also
disturbed in diseased brains, according to a study published in Journal
of Biological Chemistry last year.
findings link copper accumulation and brain disease, though not as much
research has been conducted as with iron, scientists say.
addition to iron accrual, lower-than-normal levels of zinc have been
found in patients with Alzheimer's and Parkinson's disease, according
to work by George Brewer, an emeritus professor at the University of
Michigan, and Edward Fitzgerald at the University at Albany-SUNY,
published last year in the American Journal of Alzheimer's Disease and
Other Dementias. Dr. Brewer now is a consultant to Adeona
Pharmaceuticals Inc., based in Ann Arbor, Mich., which is developing a
zinc-based treatment for Alzheimer's, he says.
Adeona, a handful of other biotechnology companies have also been
testing experimental metal-lowering drugs for treatment of Alzheimer's
or Parkinson's. But developing such drugs is tricky because it is hard
to target metals in specific parts of the brain. Simply lowering or
increasing the amount overall in the body may not be beneficial,
may play a vital role in other brain conditions.
Lippard, a chemistry professor at the Massachusetts Institute of
Technology, and colleagues from Duke University and the University of
Toronto, found zinc helps neurons communicate in the hippocampus, a
brain region involved in learning and memory. Disturbing this
interaction, or ushering zinc into a brain region where it doesn't
belong, could affect memory formation and the occurrence of epileptic
seizures, says Dr. Lippard, who studies the role of metal ions in
biology, neuroscience, and medicine. Their work was published in
September in Neuron.
important that the medical community continue to be alerted to the
connection between metal ions and neurological disease," says Dr.
Connor and his Penn State team have shown that patients with ALS have a
higher rate of mutation in a gene, HFE, that regulates iron absorption.
Carriers of the mutation have higher levels of iron in the brain and a
fourfold increase in risk of ALS, according to a 2004 study published
in the Journal of Neurological Sciences.
have also been trying to figure out why the patients with multiple
sclerosis lose the protective coating, called myelin, surrounding their
axons, the part of the nerve cell that conducts electrical impulses.
The cells responsible for making the myelin have elevated iron, making
them more vulnerable to damage and death, says Dr. Connor.
Positive and Negative
metals play vital roles in the human body, but diseases can disturb
their balance, causing harm.
function: Involved in
oxygen transport; needed to make energy for cells.
the brain: Excess levels of
iron are linked to Alzheimer's and Parkinson's diseases. Proteins and
mutations related to iron delivery or absorption appear to be connected
to Lou Gehrig's disease and multiple sclerosis.
function: Helps transport
oxygen, often works in tandem with iron.
the brain: Wilson disease
stops the body from getting rid of copper, which can cause speech
problems, tremors and muscle stiffness. Disruption in copper regulation
causes Menkes disease, which leads to abnormally low copper levels.
function: Helps make DNA
and RNA, regulates cell death, and plays a role in short-term memory
the brain: Low levels or
the presence of the metal in areas of the brain where it isn't normally
found are thought to impair memory.