Researchers have uncovered a unique connection between diabetes and
Alzheimer’s disease, providing further evidence that a disease that robs
people of their memories may be affected by elevated blood sugar,
according to scientists at Washington University School of Medicine in St. Louis.
While many earlier studies have pointed to diabetes as a possible
contributor to Alzheimer’s, the new study – in mice – shows that
elevated glucose in the blood can rapidly increase levels of amyloid
beta, a key component of brain plaques in Alzheimer’s patients. The
buildup of plaques is thought to be an early driver of the complex set
of changes that Alzheimer’s causes in the brain.
The research is published May 4 in The Journal of Clinical Investigation.
“Our results suggest that diabetes, or other conditions that make it
hard to control blood sugar levels, can have harmful effects on brain
function and exacerbate neurological conditions such as Alzheimer’s
disease,” said lead author Shannon Macauley, PhD, a postdoctoral
research scholar. “The link we’ve discovered could lead us to future
treatment targets that reduce these effects.”
People with diabetes can’t control the levels of glucose in their
blood, which can spike after meals. Instead, many patients rely on
insulin or other medications to keep blood sugar levels in check.
To understand how elevated blood sugar might affect Alzheimer’s
disease risk, the researchers infused glucose into the bloodstreams of
mice bred to develop an Alzheimer’s-like condition.
In young mice without amyloid plaques in their brains, doubling
glucose levels in the blood increased amyloid beta levels in the brain
by 20 percent.
When the scientists repeated the experiment in older mice that
already had developed brain plaques, amyloid beta levels rose by 40
Looking more closely, the researchers showed that spikes in blood
glucose increased the activity of neurons in the brain, which promoted
production of amyloid beta. One way the firing of such neurons is
influenced is through openings called KATP channels on the surface of
brain cells. In the brain, elevated glucose causes these channels to
close, which excites the brain cells, making them more likely to fire.
Normal firing is how a brain cell encodes and transmits information.
But excessive firing in particular parts of the brain can increase
amyloid beta production, which ultimately can lead to more amyloid
plaques and foster the development of Alzheimer’s disease.
To show that KATP channels are responsible for the changes in amyloid
beta in the brain when blood sugar is elevated, the scientists gave the
mice diazoxide, a glucose-elevating drug commonly used to treat low
blood sugar. To bypass the blood-brain barrier, the drug was injected
directly into the brain.
The drug forced the KATP channels to stay open even as glucose levels
rose. Production of amyloid beta remained constant, contrary to what
the researchers typically observed during a spike in blood sugar,
providing evidence that the KATP channels directly link glucose,
neuronal activity and amyloid beta levels.
Macauley and her colleagues in the laboratory of David M. Holtzman,
MD, the Andrew B. and Gretchen P. Jones Professor and head of the
Department of Neurology, are using diabetes drugs in mice with
conditions similar to Alzheimer’s to further explore this connection.
“Given that KATP channels are the way by which the pancreas secretes
insulin in response to high blood sugar levels, it is interesting that
we see a link between the activity of these channels in the brain and
amyloid beta production,” Macauley said. “This observation opens up a
new avenue of exploration for how Alzheimer’s disease develops in the
brain as well as offers a new therapeutic target for the treatment of
this devastating neurologic disorder.”
The researchers also are investigating how changes caused by
increased glucose levels affect the ability of brain regions to network
with each other and complete cognitive tasks.