How Diabetes Links to Alzheimer's Found in Salk
Institute Study
Recent studies show diabetics have a 30 to 65% higher
risk of Alzheimer’s
April 30, 2008 – Recent studies have consistently
associated diabetes with a significantly higher risk of developing
Alzheimer’s disease but the actual molecular connection between the two
has been a mystery. Now, researchers at the Salk Institute for
Biological Studies report they have identified the probable molecular
basis for the diabetes – Alzheimer’s interaction.
In a study published in the current online issue of
Neurobiology of Aging, investigators led by David R. Schubert, Ph.D.,
professor in the Cellular Neurobiology Laboratory, report that the blood
vessels in the brain of young diabetic mice are damaged by the
interaction of elevated blood glucose levels characteristic of diabetes
and low levels of beta amyloid, a peptide that clumps to form the senile
plaques that riddle the brains of Alzheimer’s patients.
Although the damage took place long before the
first plaques appeared, the mice suffered from significant memory loss
and an increase in inflammation in the brain.
“Although the toxic beta amyloid peptide was first
isolated from the brain blood vessels of Alzheimer’s patients, the
contribution of pathological changes in brain vascular tissue to the
disease has not been well studied,” says Dave R. Schubert, Ph.D.,
professor and head of the Cellular Neurobiology Laboratory.
“Our data clearly describe a biochemical mechanism
to explain the epidemiology, and identify targets for drug development.”
Alzheimer’s and diabetes are two diseases that are
increasing at an alarming rate within the U.S. population. Alzheimer’s
affects one in 10 Americans over 65 years of age and nearly 50 percent
of those over 85 years old. Similarly, 7 percent or approximately 20
million Americans have diabetes, with the vast majority of these
individuals being over 60.
Recent epidemiological studies have shown that
diabetic patients have a 30 to 65 percent higher risk of developing
Alzheimer’s disease compared to non-diabetic individuals. The increased
risk applies to both type 1 and type 2 diabetes, which share
hyperglycemia as a common pathogenic factor.
“Many studies have focused on altered insulin
signaling in the brain as a possible mechanism for the association
between Alzheimer’s disease and diabetes but researchers paid much less
attention to the direct affects of increased blood glucose levels on
brain function and the pathogenesis of Alzheimer’s,” explains lead
author Joseph R. Burdo, Ph.D., a former postdoctoral researchers in
Schubert’s lab and now an assistant professor at Bridgewater State
College in Bridgewater, Massachusetts.
To get at the bottom of the question why diabetes
predisposes people to Alzheimer’s disease as they age, the Salk
researchers Schubert, Burdo and Qi Chen, in collaboration with diabetes
expert Nigel Calcutt, a professor in UCSD’s Department of Pathology,
induced diabetes in young mice, whose genetic background predisposes
them to acquire the symptoms of Alzheimer’s with old age.
These mice suffered damage to blood vessels well
before any overt signs of Alzheimer’s disease such as nerve cell death
or the acquisition of amyloid deposits, the hallmark of the disease,
could be detected in their brains. Further experiments revealed that the
vascular damage was due to the overproduction of free radicals,
resulting in oxidative damage to the cells lining the brain’s blood
vessels.
“While all people have a low level of amyloid
circulating in their blood, in diabetics there may be a synergistic
toxicity between the amyloid and high level of blood glucose that is
leading to the problems with proper blood vessel formation,” says Burdo.
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An earlier study by Schubert and his team has
revealed that the exposure of cells to amyloid causes free radical
production prompting a clinical trial investigating whether the
antioxidant and free radical scavenger vitamin E would be beneficial for
the treatment of Alzheimer’s disease.
While this initial trial was only marginally
successful, ongoing work in Schubert’s lab centers on a new family of
drugs that has shown promise for preventing Alzheimer’s disease and
perhaps the vascular damage associated with diabetes.
Editor's Notes:
The research has been supported by grants to the
Salk Institute from the Bundy and the Shiley Foundations.
The Salk Institute for Biological Studies in La
Jolla, California, is an independent nonprofit organization dedicated to
fundamental discoveries in the life sciences, the improvement of human
health and the training of future generations of researchers. Jonas
Salk, M.D., whose polio vaccine all but eradicated the crippling disease
poliomyelitis in 1955, opened the Institute in 1965 with a gift of land
from the City of San Diego and the financial support of the March of
Dimes.
