Research Summary: We discovered impaired glycogen metabolism in tauopathy. Tau binds to glycogen, promoting its buildup and tau accumulation. Enhancing glycogen breakdown shifts metabolism toward the pentose phosphate pathway, thereby reducing oxidative stress and neurodegeneration.
First Author: Sudipta Bar is currently a postdoctoral researcher in Prof. Pankaj Kapahi’s lab at the Buck Institute for Research on Aging, Novato, CA, USA. Dr. Bar completed his Ph.D. at the Indian Institute of Science Education and Research (IISER) Kolkata under the guidance of Prof. Rupak Datta.
Lab: Prof. Pankaj Kapahi, Buck Institute for Research on Aging
Author interview
What was the core problem you aimed to solve with this research?
Tauopathies, including Alzheimer’s disease, are characterized by the abnormal aggregation of the microtubule-associated protein tau (MAPT). Despite extensive research, effective treatments for these conditions remain elusive, partly due to a limited understanding of their underlying etiology. The vast majority of Alzheimer’s cases are sporadic, arising without clear inherited genetic mutations and typically developing later in life. These late-onset forms are influenced by a complex interplay of age, lifestyle, environmental factors, dietary habits, and genetic risk. However, it remains unclear how these environmental influences contribute to tau becoming prone to aggregation. In this study, we uncover how tau interacts with a storage sugar called glycogen in the brain and identify a potential metabolic pathway that could be targeted for future therapeutic strategies.
How did you go about solving this problem?
We observed that dietary restriction can protect against neurodegeneration. Investigating the underlying mechanisms of this protective effect, we identified abnormal glycogen metabolism in neurodegenerative conditions. Using Drosophila and patient-derived induced pluripotent stem cell (iPSC) neurons, we found that breaking down accumulated glycogen is protective. Interestingly, we found that neuronal glycogen catabolism differs from that in organs such as the liver or muscle. In neurons, glycogen breakdown does not supply extra ATP but instead generates reduced glutathione via the pentose phosphate pathway to scavenge reactive oxygen species. Further studies revealed that tau physically binds to glycogen and inhibits its breakdown. We also identified upstream activators of glycogen phosphorylase (GlyP)—the key enzyme that catabolizes stored glycogen—mediated by dietary restriction, which protects neurons from degeneration. Genetic or pharmacological activation of GlyP reduced oxidative stress and extended lifespan in tauopathy models and stem cell-derived neurons.
By uncovering how neurons handle sugar, we may have identified a new therapeutic path—one that leverages cellular chemistry to combat age-related decline. As our population ages, insights like these offer hope that decoding and rebalancing the brain’s hidden sugar dynamics could lead to powerful new tools against dementia.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Our research shows that sugar stored in brain cells may hold the key to fighting Alzheimer’s and related diseases. Glycogen—the brain’s storage form of sugar—was traditionally viewed as an inactive energy reserve. However, we found that it plays an active role in protecting brain cells. In diseases like Alzheimer’s, a toxic protein called tau traps glycogen and blocks its breakdown. This buildup hinders neurons from defending against harmful molecules associated with the aging process.
The good news is that by boosting an enzyme that breaks down glycogen, we helped brain cells protect against damage and even extended lifespan in lab models.
What are the potential implications of your findings for the field and society?
There is no cure for Alzheimer’s disease-related dementia, but by discovering how neurons manage sugar metabolism, we may have unearthed a novel therapeutic strategy.
What was the exciting moment during your research?
We began our research with the discovery that dietary restriction significantly protects neurons and extends lifespan, but encountered several surprising findings as the work progressed. We found that neuronal glycogen metabolism differs from the conventional view—neuronal glycogen appears to have a regulatory role in controlling sugar utilization across metabolic pathways. Another unexpected finding was that glycogen physically binds to tau proteins.
Paper reference: Bar, S., Wilson, K.A., Hilsabeck, T.A.U. et al. Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01314-w
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