Dietary Supplement Powers Alzheimer’s-Afflicted Neurons

Mouse Study Supports Potential of Ketone-Elevating Treatment

By Brandon Levy

Tuesday, June 2, 2020

Whether from candy, soda, or fruit, sugar is the preferred source of sustenance for many people, and also for their brains. However, in patients with Alzheimer's disease, brain cells are less capable of turning sugar into energy. New IRP researchprovides evidence that this problem and the cognitive symptoms it causes could be partially solved by providing the brain with an alternative fuel.¹

Like a hybrid car, the brain is capable of running on multiple different sources of energy. Via a set of processes called ‘metabolism,’ brain cells take in certain substances from the blood and convert them into a variety of molecules that they use to keep themselves alive. The brain primarily uses blood sugar, or glucose, to do this when supplies are plentiful, but when sugar is scarce, the liver converts fat into molecules called ketones, which the brain can turn to for an alternate fuel supply.

Even before symptoms arise, the brains of patients with Alzheimer’s disease are less effective at turning blood sugar into energy. However, as long as there is plenty of sugar available in the blood from digested food, the body does not produce ketones, leaving some brain cells starving. In this way, a brain afflicted with Alzheimer’s is like a hybrid car with a leaky gasoline tank and an empty battery. Filling the tank does little to help the situation, but if you could charge the battery, the car would run just fine.

“In Alzheimer’s disease, the brain is not taking up enough glucose to fuel brain cells and allow them to do the work they do,” explains IRP staff scientist Robert Pawlosky, Ph.D., the new study’s first author. “Ketones bypass the various steps that glucose needs to go through in order to become a fuel for the cell.”

In their new study, Dr. Pawlosky and his colleagues investigated how raising levels of ketones in the blood would affect the metabolic processes and behavior of mice that have several genetic mutations linked to Alzheimer’s disease in humans. As these mice age, their brains accumulate two abnormal proteins that are a hallmark of the illness, and their brains also gradually lose the ability to turn glucose into energy. This leads to abnormal behavior, including increased anxiety and a decreased interest in exploring their surroundings.

Compared to control mice who had nothing special added to their diet, mice fed a dietary supplement that raises blood ketone levels showed an increased abundance of certain molecules created by cellular energy production in a part of the brain called the hippocampus, which is important for learning and memory and is affected early in the course of Alzheimer’s disease. These molecules included a pre-cursor to a chemical called glutamate that is important for communication between neurons, as well as a chemical called n-acetyl-aspartate, which past research has shown to be less abundant in dying neurons. Overall, these findings suggest that neurons in the hippocampus were healthier and able to produce more energy in the mice fed the ketone supplement.

The supplement-fed animals’ improved brain health was also reflected in their behavior, as they explored much more in an open environment than the control animals. Moreover, when given a choice between spending time in an area with walls and one that was open, the supplement-fed mice spent much more time in the open spaces than the control mice, an indicator of decreased anxiety since, in nature, open areas leave mice more vulnerable to predators. What’s more, levels of n-acetyl-aspartate in the hippocampus were correlated with increased exploration and reduced anxiety-related behavior, confirming that higher levels of the molecule signal more than just improved metabolism in brain cells.

“The mice with higher levels of n-acetyl-aspartate exhibited more normal behavior patterns,” Dr. Pawlosky says.

Many researchers, as well as athletes and others looking to boost their physical or cognitive capabilities, have long been interested in carbohydrate-restricting diets that force the body to produce ketones. However, such diets may be difficult for Alzheimer’s patients to stick to, and their long-term health effects are not clear. If future clinical trials confirm that a ketone supplement partially alleviates Alzheimer’s symptoms, the treatment could be much more easily implemented than a strict diet.

“A treatment based on the consumption of a ketone supplement would not force a large dietary modification but would still increase blood ketone levels enough that you would get some kind of response, especially in the early stages of the disease,” Dr. Pawlosky says. “It could move into the clinical realm quite effectively.”

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References:

[1] A Dietary Ketone Ester Normalizes Abnormal Behavior in a Mouse Model of Alzheimer's Disease. Pawlosky RJ, Kashiwaya Y, King MT, Veech RL. Int J Mol Sci. 2020 Feb 4;21(3). pii: E1044. doi: 10.3390/ijms21031044.

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