Reducing Brain Glycogen Reserves May Offer Protection Against Dementia

Reducing Brain Glycogen Reserves May Offer Protection Against Dementia

New research from the Buck Institute for Research on Aging has shed light on a potential new strategy to combat Alzheimer's disease and related dementias. The study, published in the journal Nature Metabolism, reveals that enhancing the enzyme glycogen phosphorylase (GlyP) could have a significant protective impact against the progression of these conditions.

In Alzheimer's and related dementias, neurons accumulate excessive glycogen, a stored form of glucose. This glycogen buildup impairs the neurons' ability to manage oxidative stress, a critical factor in neurodegeneration and aging. The study shows that the breakdown of neuronal glycogen ameliorates tauopathy phenotypes in flies and iPSC-derived neurons from people with FTLD-tau.

Boosting GlyP activity restores glycogen breakdown, freeing neurons to better metabolize stored sugar. This leads to enhanced detoxification of harmful reactive oxygen species (ROS), reduced oxidative damage, protection against tau protein buildup, and extended lifespan of tauopathy model organisms. GlyP activation reroutes sugar metabolism into the pentose phosphate pathway (PPP), which is crucial for generating molecules that combat oxidative damage in neurons.

These findings suggest a novel therapeutic avenue targeting brain sugar metabolism to halt or slow neurodegeneration caused by tauopathies and Alzheimer's. Importantly, GlyP levels can be naturally boosted by dietary restriction (e.g., fasting), which mimics a protective metabolic state. Some existing drugs, particularly GLP-1 receptor agonists (commonly used for weight loss and diabetes treatment), also increase GlyP activity and might hold promise as dementia therapies by mimicking dietary restriction effects.

The study opens up the possibility of developing new treatments aimed at enhancing GlyP or modulating glycogen metabolism in neurons to protect brain health and cognitive function. The research team confirmed similar glycogen accumulation and protective effects of GlyP in human neurons derived from patients with frontotemporal dementia (FTD), strengthening the potential for translational therapies.

The work was supported by various NIH grants, the Hevolution Foundation, the American Federation of Aging Research, the Larry L. Hillblom Foundation, and the Catalyst award from Alex and Bob Griswold. The abstract of the study is titled "Neuronal Glycogen Breakdown Mitigates Tauopathy via Pentose Phosphate Pathway-Mediated Oxidative Stress Reduction".

This breakthrough was demonstrated in both fruit fly models and human neuronal cells, underscoring its translational relevance and potential for clinical impact. The study highlights the value of the fly as a model system in understanding how metabolic dysregulation affects neurodegeneration. The collaborative effort included the Kapahi lab, the Schilling lab, the Seyfried lab, and the Ellerby lab.

In conclusion, enhancing GlyP activity reduces tauopathy-related neurodegeneration by clearing glycogen buildup, lowering oxidative stress, and protecting neurons. This discovery reveals a previously underappreciated role of neuronal glycogen metabolism in brain health and Alzheimer's pathology. It offers promising therapeutic potential through dietary interventions and repurposing of metabolic drugs, potentially changing the approach to Alzheimer's and related dementias.

1. The new research in the journal Nature Metabolism suggests a novel therapeutic avenue for Alzheimer's disease and related dementias, focusing on enhancing the enzyme glycogen phosphorylase (GlyP) to combat neurodegeneration caused by tauopathies.
2. In Alzheimer's and related dementias, neurons accumulate excessive glycogen, a stored form of glucose, which impairs their ability to manage oxidative stress, a critical factor in neurodegeneration and aging.
3. Boosting GlyP activity restores glycogen breakdown, freeing neurons to better metabolize stored sugar, leading to enhanced detoxification of reactive oxygen species (ROS), reduced oxidative damage, and protection against tau protein buildup, potentially extending the lifespan of tauopathy model organisms.
4. The study reveals that GlyP activation reroutes sugar metabolism into the pentose phosphate pathway (PPP), a crucial pathway for generating molecules that combat oxidative damage in neurons, thus protecting brain health and cognitive function.
5. The study, supported by various grants and foundations, shows similar glycogen accumulation and protective effects of GlyP in human neurons derived from patients with frontotemporal dementia (FTD), strengthening the potential for translational therapies in health-and-wellness, mental-health, and therapies-and-treatments for neurological-disorders.
6. Some existing drugs, particularly GLP-1 receptor agonists, increase GlyP activity and might hold promise as dementia therapies by mimicking dietary restriction effects, possibly repurposing them in the field of fitness-and-exercise and nutrition.
7. The collaborative effort between several labs unveiled the translational relevance and potential clinical impact of the fly as a model system in understanding the link between metabolic dysregulation and neurodegeneration, contributing to science and neuroscience news in medical-conditions research.

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