05.28.2015
by Salynn Boyles
Contributing Writer

Patients with type 2 diabetes have an increased risk for developing Alzheimer’s disease, and results from mouse model studies may help explain why.
The research showed that in an Alzheimer’s mouse model, elevated blood glucose leads to increases levels of amyloid beta (Abeta) peptide — the “sticky” proteins that build up in the brains of Alzheimer’s patients. A key mechanism driving this action was also identified.

The findings could lead to novel diabetes treatments targeting this pathway, wrote Shannon Macauley-Rambach, PhD, of the Washington University School of Medicine in St. Louis, and colleagues online in the Journal of Clinical Investigation.

Using the combined techniques of glucose clamping and in vivo microdialysis, the researchers doubled blood glucose levels in both young and older awake, free-moving APP/PS1 mice and measured real-time changes in Abeta, glucose, and lactate in hippocampal interstitial fluid (ISF).

In young mice with no evidence of amyloid plaques, amyloid-beta levels in ISF increased by 20%. In older mice with amyloid plaques, doubling blood glucose levels increased ISF Abeta levels by 40%.
“The hyperglycemia-dependent increase in ISF Abeta levels was 1.6-fold higher in 18-month-old mice compared with 3-month-old mice, demonstrating that older mice with significant plaque pathology respond differentially to hyperglycemic insult,” the researchers wrote.

Macauley-Rambach noted that while the glucose challenge lasted for just 4 hours, the elevated Abeta levels persisted during the 15-hour post-challenge follow-up.

“Our paper shows that even short bursts of hyperglycemia can drive Abeta production,” she said. “Even when blood sugar goes back to normal, the effect is sustained.”

Further investigation led to the identification of the ATP-sensitive potassium channel (KATP) on the brain’s surface as a key player in elevating amyloid beta in response to higher glucose exposure.

Numerous epidemiological studies have linked diabetes and Alzheimer’s disease (AD), but most earlier research exploring this association has focused on insulin and not glucose, Macauley-Rambach told MedPage Today.

“There are even clinical trials examining intranasal insulin as a preventive treatment for Alzheimer’s, but over the last 2 years or so glucose has been getting more attention,” she said. “Some preliminary data in cultures show that if you raise glucose you can also raise Abeta, but until now no one had really done the experiments in animals to show a direct link between elevated blood glucose and amyloid-beta levels in the brain.”

Macauley-Rambach explained that in addition to Abeta aggregation, decreases in glucose metabolism have been shown to occur in regions of the brain linked to Alzheimer’s disease during the years before symptoms occur.

Macauley-Rambach explained that in addition to Abeta aggregation, decreases in glucose metabolism have been shown to occur in regions of the brain linked to Alzheimer’s disease during the years before symptoms occur.

“Not only does this offer one mechanistic explanation for the epidemiological link between type 2 diabetes mellitus and Alzheimer’s disease, but it also provides a potential therapeutic target for AD,” the researchers wrote. “Given that FDA-approved drugs already exist for the modulation of KATP channels and previous work demonstrates the benefits of sulfonylureas for treatment of animal models of AD, the identification of these channels as a link between hyperglycemia and AD pathology creates an avenue for translational research in AD.”

The findings also suggest that elevated blood glucose levels that do not reach the threshold for diabetes may impact Alzheimer’s risk, Macauley-Rambach said. She cited another recent study finding that higher glucose levels may be a risk factor for dementia even in people without diabetes.

• Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 05.29.2015