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Disease and treatment

Alzheimer’s risk among diabetics provides key to cure

Why people with type 2 diabetes develop Alzheimer’s disease more often has been a mystery. The reason lies in the energy conversion in the brains of people with diabetes, but only in the hippocampus, which is where Alzheimer’s is also centred. One effect of the changes is the conversion of ketone bodies, which are associated with a fat-rich diet. These have been used recently as an alternative treatment for Alzheimer’s, Parkinson’s disease, epilepsy and concussions.

The World Health Organization estimates that 400 million people have type 2 diabetes, and they have a significantly greater risk of developing Alzheimer’s disease than other people. Nevertheless, how the body’s inability to regulate blood glucose leads to the dementia and declining brain functioning accompanying Alzheimer’s has been hard to fathom. Now Danish researchers have discovered a possible cause by investigating changes in the brains of people with diabetes.

“Diabetes changes how the brain converts energy, but apparently only substantially in the hippocampus, the part of the brain changed by Alzheimer’s disease. In addition, the changes affect how ketone bodies are converted,” explains Helle Waagepetersen, Professor, Department of Molecular and Cellular Medicine, University of Copenhagen.

Power plants on reduced power

The Danish researchers investigated how diabetes affects energy conversion in the brains of mice. They studied the use of oxygen in the brain mitochondria, which serve as the brain’s power plant. The mitochondria convert both blood glucose and the amino acids glutamate and glutamine, and this is important for the functioning of the brain.

“Glutamate and glutamine are not only important for enabling the mitochondria to channel energy in the brain. Glutamate is also an important neurotransmitter that ensures that the right signals are transmitted between the neurons. This process, converts glutamate to glutamine, which is then secreted from the astrocytes – helper cells – before being absorbed and reconverted to glutamate in the neurons.”

The glutamate–glutamine cycle and the balance between them is incredibly important in the brain, and even small changes in this metabolism therefore strongly affect how the brain functions. Previous studies have confirmed that the changes in energy metabolism and the glutamate–glutamine balance accelerate Alzheimer’s disease.

“The brain of a mouse overall shows no noticeable difference in either oxygen consumption in the mitochondria or in the balance between glutamate and glutamine. However, when we zoom in to the hippocampus, in which Alzheimer’s develops, the brains of the mice with diabetes absorb less glutamate and convert less glutamine. This imbalance may therefore partly explain why Alzheimer’s develops.”

Early diagnosis and treatment

Understanding the link between diabetes and Alzheimer’s disease is naturally interesting because knowledge on how Alzheimer’s develops may lead to developing new drugs and treatments. According to Helle Waagepetersen, this link should also increase the focus on monitoring the development of Alzheimer’s disease among people with diabetes.

“The fact that people with diabetes more often develop Alzheimer’s should alert the health professionals treating people with diabetes to notice the early signs of Alzheimer’s. Our new knowledge on the imbalance in the brain’s energy metabolism may result in learning to measure this earlier so the disease can be discovered and possible stopped. Today, Alzheimer’s is often discovered too late to be treated properly.”

The new study also provides new hope for treating people with Alzheimer’s. In addition to imbalance in the glutamate–glutamine cycle, the mice also had increased conversion of the ketone bodies. It has been shown that a high-fat diet leads to the synthesis of ketone bodies, which has good therapeutic effects on the people with several types of brain diseases.

“Dietary supplements with ketone esters result in cognitive improvements among people with Alzheimer’s. We strongly suspect that the therapeutic benefits could be even more pronounced with earlier treatment. Learning to detect the preliminary stages of these imbalances in glucose and energy metabolism in the brain might enable us to treat the people with the disease far more effectively,” concludes Helle Waagepetersen.

Impaired hippocampal glutamate and glutamine metabolism in the db/db mouse model of type 2 diabetes mellitus” has been published in Neural Plasticity, and “Improved cerebral energetics and ketone body metabolism in db/db mice” has been published in the Journal of Cerebral Blood Flow & Metabolism. In 2014, the Novo Nordisk Foundation awarded a grant to Helle Waagepetersen for the project Type 2 Diabetes is Associated with Cerebral Metabolic Alterations Leading to Cellular Energetic Deficits and Malfunction of Glutamate Homeostasis.

Helle S. Waagepetersen
Professor
The research in NeuroMet is focused on energy and amino acid metabolism in the mammalian brain. Primary mouse cell culture systems of neurons and astrocytes from cerebral cortex or cerebellum are extensively employed. In addition, acutely isolated cortical prisms, isolated mitochondria and cell lines are applied as model systems. An array of 3H, 15N and 13C isotopes are utilized in the mapping of metabolic pathways and their regulation. HPLC and mass spectrometry are key analytical tools combined with biochemical assays, protein biochemistry, molecular biology and confocal microscopy.