Fructose is added to many of our foods and drinks. And it is produced in our own brains, which seem especially keen to generate its own fructose if we consume too much of the sugar. Unfortunately, excessive fructose in the brain may contribute to Alzheimer’s disease, say scientists based at the University of Colorado Anschutz Medical Campus (CU Anschutz).

“In essence, we propose that Alzheimer’s disease is a modern disease driven by changes in dietary lifestyle in which fructose can disrupt cerebral metabolism and neuronal function,” said Richard J. Johnson, MD, a professor of medicine at CU Anschutz and the corresponding author of a paper that recently appeared in the journal Frontiers in Aging Neuroscience. The paper, titled, “Cerebral Fructose Metabolism as a Potential Mechanism Driving Alzheimer’s Disease,” suggests that inhibition of intracerebral fructose metabolism could provide a novel way to prevent and treat Alzheimer’s disease.

According to Johnson and colleagues, fructose metabolism in the brain is related to a survival mechanism. This mechanism, which lowers energy, that is, adenosine triphosphate (ATP) in cells in association with adenosine monophosphate (AMP) degradation to uric acid, protects against starvation by stimulating foraging behavior and reducing energy and oxygen demands. It can, however, be overactivated if too much fructose is consumed.

“[Chronic] stimulation in the brain leads to mitochondrial oxidative stress and local inflammation and a progressive reduction in cerebral energy levels,” the paper’s authors wrote. “While other tissues increase glycolysis to compensate for the reduced ATP, in neurons glucose is directed to the pentose phosphate shunt to generate antioxidants to combat oxidative stress-induced mitochondrial loss.”

Overactive fructose metabolism, which involves an enzyme called ketohexokinase C (KHK-C), sets off a chain of adverse developments: glucose hypometabolism, increased oxidative stress, a progressive loss of mitochondria, and (eventually) neuronal dysfunction and death.

“In this scenario,” the paper explained, “the amyloid plaques and neurofibrillary tangles are part of the inflammatory response and participate in injury, but they are not the central factors driving the disease. Theoretically, regulating KHK-C in the brain, or regulating AMP deaminase-2 (which removes AMP, thereby reducing the ability of the cell to replenish ATP levels), might provide novel ways to prevent and treat Alzheimer’s disease.”

The paper’s authors noted that when fructose metabolism is overactivated systemically, such as from excessive fructose intake, the consequences may include metabolic syndrome, obesity, and diabetes—conditions that are associated with an increased risk for Alzheimer’s disease. Although Alzheimer’s disease may occur in the absence of these conditions, the paper’s authors suspect that Alzheimer’s disease and these other conditions may have underlying mechanisms in common, mechanisms that may involve fructose.

Fructose, the scientists pointed out, is generated in tissues by activation of the aldose reductase (AR)-sorbitol dehydrogenase (SDH) pathway (polyol pathway). “The rate-limiting enzyme in fructose production is AR, but it can be induced by a variety of mechanisms, including ischemia, hyperosmolarity, alcohol, hyperglycemia, and fructose and uric acid themselves,” they detailed. “The high glycemic state associated with diabetes also activates AR in multiple tissues associated with endogenous fructose production, including the brain.”

“AR activity,” the scientists added, “is increased in the brain and other organs with aging.

“Many risk factors for Alzheimer’s disease activate endogenous fructose metabolism. … If the fructose pathway is key for the development of Alzheimer’s disease, one might expect some evidence of a relationship between conditions associated with endogenous fructose production with the development of dementia.”

“By outlining consistent evidence,” Johnson related, “we’re hoping to inspire researchers to continue exploring the relationship between fructose in the brain and Alzheimer’s disease. New treatments aimed at inhibiting intracerebral fructose metabolism could provide a novel way to prevent and treat this disease.”

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