Buck Institute study reveals how sugar breakdown in neurons supports redox balance and may counter tau-driven neurodegeneration.
Glycogen, the stored form of glucose, has traditionally been viewed as a passive energy reserve in neurons, with its primary roles attributed to liver and muscle tissues. However, recent research from the Buck Institute for Research on Aging challenges this notion, demonstrating that neuronal glycogen plays an active role in mitigating neurodegenerative diseases such as Alzheimer’s and frontotemporal dementia (FTD).
The study, published in Nature Metabolism, reveals that in models of tauopathy – a group of neurodegenerative diseases characterized by the accumulation of tau proteins – neurons accumulate excessive glycogen. This buildup appears to contribute to disease progression. The researchers found that tau proteins bind to glycogen, trapping it and preventing its breakdown. This impairs the neuron’s ability to manage oxidative stress, a key feature in aging and neurodegeneration [1].
Professor Pankaj Kapahi, PhD, senior scientist on the study, said the research challenged the view that glycogen’s role in neural activity can be considered negligible – “And it does so with striking implications,” he said. “Stored glycogen doesn’t just sit there in the brain; it is involved in pathology.”
Longevity.Technology: Glycogen in neurons has long been considered the metabolic equivalent of a rainy-day fund that never gets spent – present, yes, but not exactly pulling its weight in the fight against neurodegeneration. This new research from the Buck Institute turns that notion on its head; not only is neuronal glycogen active, it appears to be a critical regulator of oxidative stress, with its breakdown shunting glucose into the pentose phosphate pathway (PPP) to generate the very molecules needed to defang reactive oxygen species. That this mechanism operates downstream of dietary restriction – the undisputed heavyweight of geroprotective interventions – adds both biological plausibility and a certain pleasing elegance; it’s always satisfying when one sees the metabolic dots being so neatly joined.
Of course, identifying glycogen phosphorylase (GlyP) as the lever that might nudge the brain’s biochemistry toward resilience opens the door to something far more tantalizing – the prospect of therapeutic intervention that doesn’t require the self-denial of caloric restraint. There is a hint of nutrigeroscience here, of course, and more than a suggestion of pathway mimicry – those popular end-runs around the unpalatable. And while drugging metabolism is never straightforward – let’s not pretend the PPP isn’t a finicky customer – the data from both fly and human models give this target weight. One can almost see GlyP stepping up as the newest recruit to the line-up of geroscience poster children – albeit with its sleeves rolled up for the challenges ahead.
Glycogen breakdown and oxidative stress
The researchers discovered that by restoring the activity of glycogen phosphorylase (GlyP) – the enzyme responsible for initiating glycogen breakdown – they could reduce tau-related damage in both fruit flies and human stem cell-derived neurons.
Rather than using glycogen as a fuel for energy production, these enzyme-supported neurons rerouted the sugar molecules into the pentose phosphate pathway (PPP), a critical route for generating NADPH and glutathione, molecules that protect against oxidative stress.
“By increasing GlyP activity, the brain cells could better detoxify harmful reactive oxygen species, thereby reducing damage and even extending the lifespan of tauopathy model flies,” said Sudipta Bar, PhD, lead author of the study.
Dietary restriction and pharmacological mimetics
The study also demonstrated that dietary restriction (DR), a well-known intervention to extend lifespan, naturally enhanced GlyP activity and improved tau-related outcomes in flies. The researchers further mimicked these effects pharmacologically using a molecule called 8-Br-cAMP, showing that the benefits of DR might be reproduced through drug-based activation of this sugar-clearing system [1].
“This work could explain why GLP-1 drugs, now widely used for weight loss, show promise against dementia, potentially by mimicking dietary restriction,” said Kapahi.
Translational potential and collaborative efforts
The team confirmed similar glycogen accumulation and protective effects of GlyP in human neurons derived from patients with FTD, strengthening the potential for translational therapies [1]. Kapahi emphasized the collaborative nature of the research, which involved expertise in fly aging and neurodegeneration, proteomics and human induced pluripotent stem cells (iPSCs).
“Work in this simple animal allowed us to move into human neurons in a much more targeted way,” he noted.
The study highlights glycogen metabolism as an unexpected player in the brain’s defense against neurodegeneration and opens new avenues for therapeutic strategies targeting the cell’s inner chemistry to combat age-related decline.
“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,” Kapahi said. “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.”
As our understanding of the brain’s metabolic processes deepens, the role of glycogen in neuronal health emerges as a promising frontier; future research will determine whether targeting glycogen metabolism can translate into effective therapies for neurodegenerative diseases.
[1] https://www.nature.com/articles/s42255-025-01314-w
Article photographs courtesy of The Buck Institute
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