Healthcare (Commonwealth Union) – Neurodegenrative disorders such as dementia, Alzeimers diseases have had a devastating impact both on the individual and their families. Extensive research from various institutions across the world have provided much hope with new insights.
A groundbreaking study from researchers at the Buck Institute for Research on Aging has identified an unexpected factor in the fight against Alzheimer’s and other dementias: how the brain processes sugar. Published in Nature Metabolism, the findings suggest that breaking down glycogen—a stored form of glucose—within brain cells may help protect against the accumulation of harmful proteins and prevent neurodegeneration.
Glycogen is commonly known as an energy reserve stored in the liver and muscles. Although small amounts are present in the brain, primarily in support cells like astrocytes, its function in neurons has often been considered minimal. “This research turns that assumption on its head,” says senior author Professor Pankaj Kapahi, PhD. “Glycogen in the brain isn’t just inactive storage—it plays a role in disease development.”
Led by postdoctoral researcher Dr. Sudipta Bar, the team found that neurons in both fruit fly and human models of tauopathy—a class of neurodegenerative diseases that includes Alzheimer’s—show abnormal glycogen buildup. Even more crucially, this accumulation seems to accelerate disease. According to Bar, the tau protein, known for forming tangled clusters in Alzheimer’s patients, appears to attach to glycogen molecules, preventing them from being properly broken down.
Researchers of the study pointed out that the neurons lose a vital defense against oxidative stress, a major factor in aging and neurodegeneration, when glycogen cannot be broken down. The researchers discovered that they could lessen tau-related damage in fruit flies and neurons produced from human stem cells by reviving the activity of an enzyme known as glycogen phosphorylase (GlyP), which initiates the breakdown of glycogen.
These enzyme-supported neurons redirected the sugar molecules into the pentose phosphate pathway (PPP), which is essential for producing the oxidative stress-protective molecules glutathione and NADPH (nicotinamide adenine dinucleotide phosphate), instead of using glycogen as fuel for energy production. Bar indicated that the brain cells could better detoxify harmful reactive oxygen species by increasing GlyP activity, which would reduce damage and even extend the lifespan of tauopathy model flies.
More encouragingly, the group showed that dietary restriction (DR), a well-known strategy to increase lifespan, improved tau-related outcomes in flies and naturally increased GlyP activity. They then used a chemical called 8-Br-cAMP to pharmacologically duplicate similar results, demonstrating that the advantages of DR could be replicated by activating this sugar-clearing system using a medication. Kapahi indicated that this research may help explain why GLP-1 medications, which are currently commonly used to help people lose weight, may be effective in preventing dementia by simulating dietary restriction.
The scientists also observed comparable glycogen buildup and the protective role of GlyP in human neurons derived from individuals with frontotemporal dementia (FTD), reinforcing the promise for future therapeutic applications. Kapahi highlighted that the study showcases the effectiveness of using fruit flies as a model to reveal how metabolic imbalances contribute to neurodegenerative diseases. “Work in this simple animal allowed us to move into human neurons in a much more targeted way,” he added.
Kapahi stated that the research did not just highlight glycogen metabolism as an unexpected hero in the brain but also leads the way to a new direction in the search for treatments for Alzheimer’s and related diseases. “By discovering how neurons manage sugar, we may have unearthed a novel therapeutic strategy: one that targets the cell’s inner chemistry to fight age-related decline,” he added. “As we continue to age as a society, findings like these offer hope that better understanding—and perhaps rebalancing—our brain’s hidden sugar code could unlock powerful tools for combating dementia”.
