Our story begins with a simple but powerful observation from our lab’s long-standing work on dietary restriction (DR). We found that DR dramatically rescues neurodegeneration in fruit flies expressing human tau protein—a model for tauopathy. This wasn't something we observed in flies expressing amyloid-beta, which made the tau-specific interaction particularly intriguing. Given our lab's deep interest in how DR modulates aging and disease through tissue-specific pathways, this result immediately raised new questions: Why would dietary restriction selectively protect against tauopathy? What molecular pathways might underlie this effect?
To probe further, we turned to proteomics. We compared protein changes in the brains of flies on a rich diet and those overexpressing human tau. Remarkably, we found a significant overlap in the affected proteins, pointing to shared pathways between dietary excess and tau-induced toxicity. This convergence suggested that tauopathy might represent a state of altered metabolic regulation—one that is responsive to dietary inputs. It raised a tantalizing possibility: could metabolic interventions like intermittent fasting reduce tau pathology in humans?
One cluster of altered proteins stood out to us—enzymes involved in glycogen metabolism. Although glycogen has traditionally been viewed as an energy store for astrocytes, recent evidence hints that neurons also contain glycogen, particularly under stress. However, its role in the brain—and especially in disease—remains poorly understood.
We saw this as an opportunity. Rather than pursuing well-established pathways, we chose to explore glycogen, a target that had been largely overlooked in the context of neurodegeneration. It was a risk, but it paid off.
First, we confirmed that glycogen-related enzymes were not only altered in tau-expressing fly brains but also in human Alzheimer’s disease brain proteomes. Then, we turned to patient-derived iPSC neurons carrying tau mutations. To our encouragement, these cells also showed increased glycogen accumulation, reinforcing the idea that tau influences glycogen homeostasis in a conserved manner across species.
Our initial assumption was that glycogen builds up in Alzheimer’s because neurons are starved for glucose. But when we activated glycogen breakdown using glycogen phosphorylase (PYGB), an enzyme first described by Carl and Gerty Cori in their Nobel-winning work, we were surprised again.
Rather than enhancing glycolysis and energy production, glycogen breakdown reduced glycolytic flux. Instead, we saw an unexpected activation of the pentose phosphate pathway (PPP)—a critical metabolic route that generates NADPH, which protects cells from oxidative stress. This discovery reframed glycogen’s role in neurons: not as an energy source, but as a modulator of redox balance. Consistently, we found that activating glycogen breakdown reduced reactive oxygen species, while blocking the PPP eliminated this protective effect.
We then asked: why does glycogen accumulate in tauopathy in the first place? Our results revealed a surprising interaction: glycogen binds to tau, a key protein implicated in Alzheimer’s pathology. This co-aggregation could worsen disease by trapping glycogen in pathological tau tangles, blocking its beneficial breakdown and fueling a vicious cycle of oxidative stress and degeneration.
Another intriguing result came from dietary studies. We discovered that dietary protein restriction activates cAMP signaling, a known upstream regulator of glycogen phosphorylase. This pathway increased glycogen breakdown and reduced tau pathology, highlighting a novel connection between nutrient sensing and glycogen-driven neuroprotection. The implications are broad—dietary strategies may have untapped potential in modulating neuronal metabolism to combat neurodegeneration.
Finally, we explored how glycogen metabolism might influence broader cellular functions. Metabolomic analysis revealed that glycogen breakdown decreases acetyl-CoA and increases UDP-N-acetylglucosamine, two critical metabolites that regulate protein post-translational modifications like acetylation and O-GlcNAcylation. These changes may influence tau aggregation and cellular stress responses, suggesting that glycogen breakdown impacts not only redox status but also epigenetic and proteostasis pathways.
Together, these findings shift the paradigm: glycogen in the brain is not just a backup fuel—it’s a regulatory hub. By breaking it down, neurons can engage protective pathways, reduce oxidative damage, and modulate protein homeostasis.
This work also underscores the power of cross-species approaches. From fly genetics to human iPSC neurons, and leveraging large-scale brain proteomic datasets, we built a cohesive picture of a metabolic axis that had been hiding in plain sight. The fruit fly was instrumental—not just in confirming our hypotheses, but in guiding us to the right questions. We’ve long believed that underexplored pathways often harbor the most exciting biology. Glycogen proved to be one such example.
Of course, many questions remain. How is glycogen turnover regulated in different brain regions or cell types? Does its binding to tau drive disease progression, or is it a compensatory response? Can we harness this pathway pharmacologically in humans? And how do downstream metabolic shifts in acetyl-CoA and UDP-GlcNAc affect tau modifications and neuronal survival?
This study is just the beginning. We believe these insights open a promising new frontier in the study of brain metabolism and neurodegeneration—and we hope they inspire others to reconsider the metabolic stories still left to uncover. Read the full story here: