HMN 2025: How Discovery provides new hope for combating neurodegeneration

A brand new study from scientists on the Buck Institute for Research on Aging has revealed a stunning participant within the battle towards Alzheimer’s illness and different types of dementia: mind sugar metabolism. Published in Nature Metabolism, the analysis uncovers how breaking down glycogen—a saved type of glucose—in neurons could shield the mind from poisonous protein buildup and degeneration.

Glycogen is often regarded as a reserve vitality supply saved within the liver and muscular tissues. While small quantities additionally exist within the mind, significantly in assist cells referred to as astrocytes, its position in neurons has lengthy been dismissed as negligible.

“This new study challenges that view, and it does so with putting implications,” says Professor Pankaj Kapahi, Ph.D., senior scientist on the research. “Stored glycogen would not simply sit there within the mind; it’s concerned in pathology.”

The analysis group, led by postdoc Sudipta Bar, Ph.D., found that in each fly and human models of tauopathy (a gaggle of neurodegenerative ailments together with Alzheimer’s), neurons accumulate extreme glycogen. More importantly, this buildup seems to contribute to illness development. Bar says tau, the notorious protein that clumps into tangles in Alzheimer’s sufferers, seems to bodily bind to glycogen, trapping it and stopping its breakdown.

When glycogen cannot be damaged down, the neurons lose an important mechanism for managing oxidative stress, a key characteristic in ageing and neurodegeneration. By restoring the exercise of an enzyme referred to as glycogen phosphorylase (GlyP)—which kicks off the method of glycogen breakdown—the researchers discovered they might scale back tau-related harm in fruit flies and human stem cell-derived neurons.

Rather than utilizing glycogen as a gas for vitality manufacturing, these enzyme-supported neurons rerouted the sugar molecules into the pentose phosphate pathway (PPP)—a vital route for producing NADPH (nicotinamide adenine dinucleotide phosphate) and Glutathione, molecules that shield towards oxidative stress.

“By rising GlyP exercise, the mind cells might higher detoxify dangerous reactive oxygen species, thereby decreasing harm and even extending the lifespan of tauopathy model flies,” mentioned Bar.

Even extra promising, the group demonstrated that dietary restriction (DR)—a well known intervention to increase lifespan—naturally enhanced GlyP exercise and improved tau-related outcomes in flies. They additional mimicked these results pharmacologically utilizing a molecule referred to as 8-Br-cAMP, displaying that the advantages of DR is likely to be reproduced via drug-based activation of this sugar-clearing system.

“This work might clarify why GLP-1 medication, now broadly used for weight reduction, present promise towards dementia, doubtlessly by mimicking dietary restriction,” mentioned Kapahi.

Researchers additionally confirmed related glycogen accumulation and protecting results of GlyP in human neurons derived from sufferers with frontotemporal dementia (FTD), strengthening the potential for translational therapies. Kapahi says the research emphasizes the ability of the fly as a model system in uncovering how metabolic dysregulation impacts neurodegeneration.

“Work on this easy animal allowed us to maneuver into human neurons in a way more focused method,” he mentioned.

Kapahi additionally acknowledges the Buck’s extremely collaborative environment as a significant factor within the work. His lab, with experience in fly ageing and neurodegeneration, took benefit of proteomics experience within the Schilling lab and the Seyfried lab (at Emory University) in addition to the Ellerby lab, which has experience in human iPSCs and neurodegeneration.

Kapahi says this study not solely highlights glycogen metabolism as an surprising hero within the mind but additionally opens up a brand new path within the seek for therapies towards Alzheimer’s and associated ailments. “By discovering how neurons handle sugar, we could have unearthed a novel therapeutic technique: one which targets the cell’s inside chemistry to combat age-related decline,” he says.

“As we proceed to age as a society, findings like these supply hope that higher understanding—and maybe rebalancing—our mind’s hidden sugar code might unlock highly effective instruments for combating dementia.”