Of dozens of candidates potentially involved in
increasing a person's risk for the most common
type of Alzheimer's disease, which affects more than 5
million Americans over the age of 65, one gene
that keeps grabbing the attention of Johns Hopkins
researchers makes a protein called neuroglobin.
Adding to a growing body of evidence about the
importance of this protein for the health of the
aging brain, researchers at the
McKusick-Nathans Institute of Genetic Medicine at the
Johns Hopkins
University School of Medicine canvassed the genetic
neighborhood of neuroglobin and, for the first
time in a human population, linked variation there with a
risk for Alzheimer's.
Ever so slight genetic variations between individuals
can and do influence the amounts of
particular proteins that each specific gene ultimately
produces. In this case, the team has found that
individuals with genetic variations equating to less
neuroglobin production have an increased risk for
Alzheimer's.
"An intriguing part of this study was the high levels
of neuroglobin that we found in the
Alzheimer's brain, which was exactly the opposite from what
we expected," said Dimitrios
Avramopoulos, an associate professor in the Institute of
Genetic Medicine and the
Department of Psychiatry at Johns Hopkins.
Referring to data published in Neurobiology of Aging,
Avramopoulos said that his team
measured levels of gene product in 56 different samples of
human brain tissue: 30 from confirmed
cases of Alzheimer's and 26 without brain disease.
The scientists found that neuroglobin levels decreased
with advancing age, which, Avramopoulos
points out, is consistent with risk of Alzheimer's
increasing with advancing age. They also found that
levels of neuroglobin were lower in women than in men,
which is consistent with the fact that women
have a slightly higher risk of Alzheimer's. About two times
as many patients in the general population
with Alzheimer's are women, a statistic which, in part, can
be attributed to the fact that women live
longer and therefore have more of a chance to get
Alzheimer's. Having corrected for that disparity,
researchers have noted a slightly higher risk in women than
in men.
They say they were surprised to find that neuroglobin
levels were higher in the brain tissue
from Alzheimer's patients than that of the control
group.
Counterintuitive though it seemed at first, it
actually makes sense, Avramopoulos says,
especially in light of previously published studies that
indicated a protective function for neuroglobin
and showed that mouse brains respond to stress — in
this case, a lack of oxygen — by producing more
neuroglobin.
The scientists think that neuroglobin production also
ramps up in reaction to the insult of the
Alzheimer's disease. They hypothesize that maybe in some
people it's simply not enough of a
protective response to effectively defend the brain. "The
older we get, the less neuroglobin this
particular gene produces in our brains — unless
something stimulates the gene to produce more,"
Avramopoulos said. "That something could be a stressor such
as a lack of oxygen resulting from stoke
or emphysema, for instance. And it looks like it also could
be Alzheimer's disease.
"Further work on this gene will likely provide
intervention targets for a multitude of very
common conditions, including Alzheimer's," he said.
In addition to Avramopoulos, authors of the paper are
Megan Szymanski, Ruihua Wang, M.
Danielle Fallin and Susan S. Bassett, all of Johns
Hopkins.
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