Neurology researchers Shannon Macauley, PhD, David Holtzman, MD, and colleagues at Washington University School of Medicine in St. Louis, have discovered a unique connection between Alzheimer’s disease and diabetes. The scientists’ research, using mouse models, suggests that elevated blood sugar can harm brain function.
While many earlier studies have pointed to diabetes as a possible contributor to Alzheimer’s, an increasingly prevalent disease that robs people of their short-term memories, this new study in mice reveals that elevated glucose levels in the blood can rapidly increase levels of amyloid beta, a key component of the brain plaques that manifest in Alzheimer’s patients. These plaque buildups are thought to be an early driver of the complex set of changes that Alzheimer’s causes in the brain.
The research was published online May 4 in The Journal of Clinical Investigation, in a Brief Report article entitled: “Hyperglycemia modulates extracellular amyloid- concentrations and neuronal activity in vivo“ (J Clin Invest. doi:10.1172/JCI79742), coauthored by Shannon L. Macauley, Molly Stanley, Emily E. Caesar, Steven A. Yamada, Marcus E. Raichle, Ronaldo Perez, Thomas E. Mahan, Courtney L. Sutphen, and David M. Holtzman, of the Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, at Washington University School of Medicine, St. Louis, Missouri. Marcus E. Raichle is also associated with the WUStL Medicine Department of Radiology,
The coauthors note that epidemiological studies show that patients who have type-2-diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose, have an increased risk for developing dementia, particularly dementia due to Alzheimer’s disease (AD). They deduce that these observations suggest abnormal glucose metabolism likely playing a role in some aspects of AD pathogenesis, leading the researchers to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine (mouse) models.
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. By combining glucose clamps with in vivo microdialysis, they were able to modulate blood glucose levels in awake, freely moving APP/PS1 mice while simultaneously investigating changes in A, glucose, and lactate within the hippocampal ISF. Their data demonstrate that elevated blood glucose levels affect hippocampal metabolism, neuronal activity, and ISF A concentrations in young mice lacking any appreciable amyloid plaques in their brains, doubling glucose levels in the blood increased amyloid beta levels in the brain by 20 percent. However, when the scientists repeated the experiment in older mice that already had developed brain plaques, amyloid beta levels rose by 40 percent and the effect of hyperglycemia on ISF A is exacerbated, suggesting that age- or pathology-dependent changes result in an alteration of the brain’s response to a metabolic insult.
With their findings pointing to acute hyperglycemia raising interstitial fluid (ISF), the researchers explored the role of inward rectifying, ATP-sensitive potassium openings on the surface of brain cells (KATP) called KATP channels as one mechanism linking glucose metabolism, neuronal excitability, and ISF with resulting data suggesting that KATP channels can mediate response of hippocampal neurons to elevated blood glucose levels by coupling changes in metabolism with neuronal activity and ISF A.
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 by KATP channels. 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.
In addition, their work suggests that KATP channels within the hippocampus act as metabolic sensors and couple alterations in glucose concentrations with changes in electrical activity and extracellular A levels. Not only does this offer one mechanistic explanation for the epidemiological link between T2DM and AD, but it also provides a potential therapeutic target for AD.
The scientists note that with FDA-approved drugs already existing for the modulation of KATP channels and previous work demonstrating the benefits of sulfonylureas for treating animal models of AD, identification of these channels as a link between hyperglycemia and AD pathology creates an avenue for translational AD research.
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.
“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,” says 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.”
“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,” Dr. Macauley says. “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 data also suggest that repeated episodes of transient hyperglycemia, such as those found in T2DM, could both initiate and accelerate plaque accumulation — thus, the correlation between hyperglycemia and increased ISF A provides one potential explanation for the increased risk of AD and dementia in T2DM patients or individuals with elevated blood glucose levels.
Dr. Macauley and her colleagues in the laboratory of David M. Holtzman, MD the the Andrew B. and Gretchen P. Jones Professor, Professor of Developmental Biology, Associate Director of the Alzheimer’s Disease Research Center, and a member of the Hope Center for Neurological Disorders and head of the Department of Neurology, are using diabetes drugs in mice with conditions similar to Alzheimer’s to further explore this connection.
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.
The WUStL 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.
The research was supported by the National Institutes of Health (NIH), grants F32 NS080320, P01 NS080675; the National Science Foundation (NSF), grant DGE-1143954; and the JPB Foundation.
Washington University School of Medicine at St. Louis
The Journal of Clinical Investigation
Washington University School of Medicine at St. Louis