Researchers Identify Brain Protein That Halts
Progression Of Alzheimer's
Researchers have identified a protein in the brain that halts the
progression of Alzheimer’s disease in human brain tissue.
The protein, known as “transthyretin,” protects brain
cells from gradual deterioration by blocking another toxic protein
that contributes to the disease process.
The National Institute of Environmental Health Sciences, a component
of the National Institutes of Health, provided $1.25 million to University
of Wisconsin-Madison scientists for the transthyretin study. The
scientists will present their findings October 26 at the 34th annual
meeting of the Society for Neuroscience in San Diego, Calif.
“The results of this study are promising,” said Kenneth
Olden, Ph.D., director of the NIEHS. “More studies are needed
to understand how transthyretin can be used in treating Alzheimer’s
patients.”
Alzheimer’s disease progresses when a toxic protein, known
as “beta-amyloid,” attacks the brain’s nerve cells
involved in learning and memory. The beta-amyloid creates sticky
plaques and tangles that gradually disable nerve cells, producing
memory loss. Transthyretin appears to protect brain cells by intercepting
the beta-amyloid and preventing it from interacting with the brain
tissue.
“Based on the results of animal studies, we know that the
disease process depends in large part on the delicate balance between
the ‘good’ transthyretin protein and the ‘bad’
beta-amyloid protein,” says Dr. Jeff Johnson, associate professor
at the University of Wisconsin’s School of Pharmacy and lead
author on the study. “In Alzheimer’s patients, the ‘bad’
proteins significantly outnumber the ‘good’ proteins.”
Johnson discovered the effect of transthyretin while studying mice
genetically engineered with defective genes taken from human patients
with early-onset Alzheimer’s disease. As expected, the defective
genes produced mice with higher-than-normal levels of the toxic
beta-amyloid protein. These mice did not, however, exhibit symptoms
of Alzheimer’s disease.
“We have a mouse whose brain is bathing in toxic beta-amyloid
without exhibiting disease symptoms,” says Johnson. “We
were all asking the same question Why aren’t these nerve cells
dying?”
Dr. Thor Stein, a researcher in Johnson’s laboratory and
first author of the study, then analyzed the brains of mice and
noticed that the levels of transthyretin had increased dramatically.
When Stein treated the mouse brain with an antibody that prevented
transthyretin from reacting with the beta-amyloid protein, the mice
showed brain cell death. “We concluded that the transthyretin must have protected the
brain cells from the toxic effects of the beta-amyloid,” says
Johnson.
Test tube studies with cultured brain cells from human cortex support
the findings. When Stein treated human brain cells with the transthyretin
protein, then exposed the cells to the toxic beta-amyloid, the brain
cell death was minimal. “Now that we have demonstrated that
this protective mechanism is relevant to humans, we can start to
identify strategies to slow nerve degeneration in Alzheimer’s
patients,” says Johnson.
According to Johnson, this would involve developing drugs that
would boost the transthyretin within the brain or methods depositing
transthyretin into the brain. “Hopefully this research will
inspire a new approach to the treatment of Alzheimer’s, one
focused on preventing the loss of the brain cells instead of treating
the resulting symptoms.”
Johnson foresees a time when family members with a genetic predisposition
to Alzheimer's disease could take a yet-undeveloped drug to increase
transthyretin protein and prevent the disease from developing. Theoretically,
the drug also could be given in the early stages of Alzheimer’s
to stop progression of the disease, preserving a higher level of
cognitive function in patients.
The transthyretin discovery will likely impact the screening of
environmental chemicals for their potential role in causing or exacerbating
Alzheimer’s disease. “Researchers could develop tests
that determine whether a particular chemical or agent in the environment
is able to shift the delicate balance between the ‘good’
and ‘bad’ proteins,” notes Johnson. “This
would allow scientists to establish definitive links between environmental
exposures and Alzheimer’s disease pathology.”
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