Summary: New research from the Buck Institute identifies a previously underappreciated role for neuronal sugar metabolism in protecting the brain from Alzheimer’s disease and other tau-related dementias. The study shows that neurons in both fruit fly and human models of tauopathy accumulate excess glycogen, and when this stored sugar cannot be broken down it impairs cells’ ability to manage oxidative stress and accelerates neurodegeneration.
Restoring the activity of the enzyme glycogen phosphorylase (GlyP) redirected glucose derived from glycogen into the pentose phosphate pathway (PPP), boosting antioxidant capacity, lowering oxidative damage, and improving outcomes in model organisms. The researchers also found that dietary restriction and pharmacological agents that mimic its effects can enhance GlyP activity and replicate these protective benefits.
Key findings
- Neuronal glycogen accumulation: Neurons in tauopathy models, including flies and human iPSC-derived neurons, accumulate excessive glycogen that correlates with disease markers.
- Disrupted stress response: When glycogen is trapped and cannot be degraded, neurons lose an important route for generating reducing power needed to neutralize reactive oxygen species.
- Protective rerouting of glucose: Activating glycogen phosphorylase pushes glucose into the pentose phosphate pathway, increasing NADPH and glutathione availability and lowering oxidative stress.
- Translational potential: Dietary restriction enhanced GlyP activity and improved tau-associated phenotypes in flies, and a cAMP analog (8‑Br‑cAMP) replicated DR effects pharmacologically. Similar protective mechanisms were observed in human neurons from patients with frontotemporal dementia.
Source: Buck Institute
A team led by postdoctoral researcher Sudipta Bar, PhD, working with senior scientist Professor Pankaj Kapahi, PhD, published these findings in Nature Metabolism. Their work overturns the long-standing assumption that glycogen in neurons is negligible and functionally insignificant. Instead, the study reveals that neuronal glycogen metabolism plays a pivotal role in how neurons cope with oxidative stress and proteinopathy associated with tau-driven neurodegeneration.
Glycogen is traditionally viewed as a storage form of glucose concentrated in liver and muscle, with modest stores in brain support cells called astrocytes. This study demonstrates that neurons themselves can accumulate glycogen in disease states and that this accumulation becomes harmful when glycogen is not properly mobilized.
Bar and colleagues provide evidence that tau protein physically associates with glycogen, effectively trapping it and preventing its normal breakdown. This sequestration sets off a harmful cycle: trapped glycogen impairs the cell’s ability to produce NADPH via the pentose phosphate pathway, reducing antioxidant defenses and promoting further tau pathology and cellular dysfunction.
By genetically or pharmacologically enhancing glycogen phosphorylase (GlyP), the researchers restored glycogen breakdown in neurons. Instead of funneling resulting glucose into glycolytic energy production, the glucose was shunted into the PPP, increasing the production of NADPH and glutathione—key molecules that neutralize reactive oxygen species. The net effect was lower oxidative damage, improved cellular health, and extended lifespan in tauopathy model flies.
Importantly, the protective mechanism translated to human neurons derived from patients with frontotemporal dementia, supporting the idea that targeting neuronal glycogen metabolism could be a viable therapeutic strategy for human neurodegenerative disease.
The team also explored lifestyle and drug-related interventions. Dietary restriction, an intervention known to extend lifespan across species, naturally boosted GlyP activity in flies and improved tau-related metrics. The researchers reproduced these benefits using the membrane-permeable cAMP analog 8‑Br‑cAMP, suggesting the molecular effects of dietary restriction might be pharmacologically mimicked to activate the same sugar-clearing pathway.
Professor Kapahi and collaborators highlight the value of Drosophila as an efficient model for uncovering metabolic mechanisms that are relevant to human neurodegeneration. Their work combined expertise in fly aging, proteomics, and human induced pluripotent stem cell (iPSC) models to move rapidly from discovery to human-relevant experiments.
This research positions impaired neuronal glycogen metabolism as a hallmark of tauopathies and identifies GlyP activation and PPP rerouting as promising, mechanistically grounded targets for future therapies. By focusing on how neurons manage stored sugar and use it to maintain redox balance, the study opens a new avenue for interventions that could slow or prevent the progression of Alzheimer’s disease and related dementias.
Coauthors: Kenneth A. Wilson, Tyler A.U. Hilsabeck, Sydney Alderfer, Jordan B. Burton, Samah Shah, Anja Holtz, Enrique M. Carrera, Jennifer N. Beck, Jackson H. Chen, Grant Kauwe, Tara E. Tracy, Birgit Schilling, Lisa M. Ellerby, Eric B. Dammer, Fatemeh Seifar, Nicholas T. Seyfried, Ananth Shantaraman and others contributed to this multidisciplinary study.
Funding: The work received support from multiple NIH grants (including R01AG038688, R21AG054121, R01AG071995 and others) and from foundations such as the Hevolution Foundation, the American Federation for Aging Research, the Larry L. Hillblom Foundation and the CatalystX award from Alex and Bob Griswold.
About this metabolism and dementia research news
Author: Kris Rebillot
Source: Buck Institute
Contact: Kris Rebillot – Buck Institute
Image: Credit to Neuroscience News
Original Research: Closed access. “Neuronal Glycogen Breakdown Mitigates Tauopathy via Pentose Phosphate Pathway‑Mediated Oxidative Stress Reduction” by Sudipta Bar et al., Nature Metabolism.
Abstract
Neuronal Glycogen Breakdown Mitigates Tauopathy via Pentose Phosphate Pathway‑Mediated Oxidative Stress Reduction
Tauopathies, including Alzheimer’s disease and frontotemporal lobar degeneration with tau inclusions, lack effective treatments. This study reveals impaired glycogen metabolism in a tauopathy Drosophila model and in people with Alzheimer’s disease, linking tau pathology to disrupted glycogen handling. Promoting neuronal glycogen breakdown ameliorates disease phenotypes in flies and in iPSC‑derived neurons from patients with FTLD‑tau by redirecting glucose flux into the pentose phosphate pathway and reducing oxidative stress. Mechanistically, tau appears to bind glycogen and promote its accumulation, creating a feedback loop that worsens neuronal homeostasis. These results identify impaired glycogen metabolism as a hallmark of tauopathies and suggest that targeting glycogen breakdown and PPP flux is a promising therapeutic approach for tau‑related neurodegenerative disease.