Neurons Burn Sugar Differently, New Discovery Could Protect the Brain
A new study reveals how neurons process sugar differently.
Complete the form below to unlock access to ALL audio articles.
New research published in Nature Metabolism has identified a previously underestimated contributor to tau-related neurodegenerative conditions, including Alzheimer’s disease and frontotemporal dementia. The study implicates neuronal glycogen metabolism as a potentially protective mechanism when functioning correctly, and a harmful one when disrupted.
Glycogen, the stored form of glucose, is usually associated with the liver and muscle tissues. In the brain, it has traditionally been considered to exist only in minor quantities within support cells known as astrocytes. The role of glycogen in neurons themselves has received relatively little attention, with longstanding assumptions suggesting its presence is negligible.
In the current study, researchers from the Buck Institute for Research on Aging re-examined that notion. Using both Drosophila melanogaster (fruit fly) and human stem cell-derived models of tauopathy – a group of diseases marked by tau protein aggregation – they found abnormal accumulations of glycogen within neurons. These accumulations correlated with a decline in cellular health and function.
Tauopathy
A class of neurodegenerative diseases characterized by the abnormal accumulation of tau protein within brain cells.
Tau protein disrupts glycogen clearance
The work demonstrated that the tau protein, commonly observed in tangle formations in Alzheimer’s disease, binds directly to glycogen molecules. This interaction appears to physically block glycogen breakdown by inhibiting access to glycogen phosphorylase (GlyP), the enzyme responsible for initiating glycogen metabolism.
Glycogen phosphorylase (GlyP)
An enzyme that breaks down glycogen into glucose-1-phosphate. This is the first step in making stored sugar available for metabolic processes.Failure to degrade glycogen was linked to increased vulnerability to oxidative stress in the neuronal environment. Cells lacking adequate GlyP activity showed higher levels of reactive oxygen species – chemically reactive molecules that can damage cellular structures.
Oxidative stress
A condition in which cells accumulate damaging reactive oxygen species due to an imbalance between their production and the body’s ability to detoxify them.Redirecting metabolism for neuroprotection
The authors restored GlyP function in fruit flies and human neurons by either genetic manipulation or chemical stimulation. This intervention did not funnel glycogen-derived glucose into energy production via glycolysis, but instead rerouted it into the pentose phosphate pathway. This alternative metabolic route generates NADPH and glutathione, both of which are involved in detoxifying oxidative stress.
Pentose phosphate pathway (PPP)
A cellular metabolic pathway parallel to glycolysis. It is critical for generating NADPH and ribose sugars used in nucleotide synthesis and for maintaining redox balance.Animals and cells treated in this way showed reduced tau-related damage. In Drosophila, lifespan was also extended. These outcomes highlight an underappreciated use of glycogen in neurons – not as a fuel source, however as a component in redox regulation.
Caloric restriction and pharmacological parallels
Dietary restriction (DR), a known lifespan-extending intervention, was shown to activate GlyP in fruit fly models. The researchers were able to replicate this effect with the administration of a molecule called 8-Br-cAMP, which mimics DR’s metabolic influence. These findings suggest that pharmacological modulation of glycogen metabolism could offer similar neuroprotective benefits to dietary changes.
Proteomics: Tools, Techniques and Translational Potential
Proteomics continues to evolve rapidly, offering powerful tools to unravel complex biological systems. This eBook explores key methodologies and innovations reshaping proteomics, from foundational techniques to AI-enhanced data analysis.View eBook
The implications for existing drug classes such as glucagon-like peptide-1 (GLP-1) receptor agonists, which mimic some aspects of DR, are notable. The study suggests a potential mechanistic explanation for emerging evidence that GLP-1 agonists may offer benefits for neurodegenerative diseases.
Relevance to human disease models
To strengthen translational relevance, the team extended their analysis to neurons derived from individuals with frontotemporal dementia. Similar glycogen accumulation and responses to GlyP modulation were observed, indicating the process is not limited to fly models.
The research underscores the importance of simple model organisms like Drosophila for identifying metabolic pathways relevant to human neurodegenerative disorders. Cross-laboratory collaboration played a key role, integrating proteomic analyses and human cell biology expertise.
This work reframes glycogen metabolism as more than an inert energy reserve. When disrupted, it may actively contribute to disease processes, offering a new metabolic target for future interventions.
Reference: Bar S, Wilson KA, Hilsabeck TAU, et al. Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction. Nat Metab. 2025. doi: 10.1038/s42255-025-01314-w
This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here.
This content includes text that has been generated with the assistance of AI. Technology Networks' AI policy can be found here.
