A brand new research from scientists on the Buck Institute for Analysis on Getting old has revealed a stunning participant within the battle in opposition to Alzheimer’s illness and different types of dementia: mind sugar metabolism. Revealed in Nature Metabolism, the analysis uncovers how breaking down glycogen — a saved type of glucose — in neurons might shield the mind from poisonous protein buildup and degeneration.
Glycogen is often considered a reserve power supply saved within the liver and muscle groups. Whereas small quantities additionally exist within the mind, notably in help cells known as astrocytes, its position in neurons has lengthy been dismissed as negligible. “This new research challenges that view, and it does so with placing implications,” says Professor Pankaj Kapahi, PhD, senior scientist on the research. “Saved glycogen does not simply sit there within the mind; it’s concerned in pathology.”
The analysis staff, led by postdoc Sudipta Bar, PhD, found that in each fly and human fashions of tauopathy (a bunch of neurodegenerative illnesses together with Alzheimer’s), neurons accumulate extreme glycogen. Extra 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 a vital mechanism for managing oxidative stress, a key characteristic in ageing and neurodegeneration. By restoring the exercise of an enzyme known as glycogen phosphorylase (GlyP) — which kicks off the method of glycogen breakdown — the researchers discovered they may scale back tau-related injury in fruit flies and human stem cell-derived neurons.
Quite than utilizing glycogen as a gas for power manufacturing, these enzyme-supported neurons rerouted the sugar molecules into the pentose phosphate pathway (PPP) — a important route for producing NADPH (nicotinamide adenine dinucleotide phosphate) and Glutathione, molecules that shield in opposition to oxidative stress. “By growing GlyP exercise, the mind cells might higher detoxify dangerous reactive oxygen species, thereby decreasing injury and even extending the lifespan of tauopathy mannequin flies,” stated Bar.
Much more promising, the staff demonstrated that dietary restriction (DR) — a widely 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 known as 8-Br-cAMP, exhibiting that the advantages of DR is likely to be reproduced by way of drug-based activation of this sugar-clearing system. “This work might clarify why GLP-1 medication, now extensively used for weight reduction, present promise in opposition to dementia, doubtlessly by mimicking dietary restriction,” stated 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 facility of the fly as a mannequin 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 stated.
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 College) in addition to the Ellerby lab which has experience in human iPSCs and neurodegeneration.
Kapahi says this research not solely highlights glycogen metabolism as an sudden hero within the mind but in addition opens up a brand new route within the seek for remedies in opposition to Alzheimer’s and associated illnesses. “By discovering how neurons handle sugar, we might have unearthed a novel therapeutic technique: one which targets the cell’s inside chemistry to struggle age-related decline,” he says. “As we proceed to age as a society, findings like these provide hope that higher understanding — and maybe rebalancing — our mind’s hidden sugar code might unlock highly effective instruments for combating dementia.”
Coauthors: Further Buck collaborators embrace 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, and Lisa M. Ellerby. Different collaborators embrace Eric B. Dammer, Fatemeh Seifar and Nicholas T. Seyfried, Emory Heart for Neurodegenerative Illness, Emory College College of Drugs, Atlanta, GA in addition to Ananth Shantaraman, Division of Biochemistry, Emory College College of Drugs, Atlanta, GA
Acknowledgments: The work was supported by NIH grants R01AG038688, R21AG054121, AG045835, R01AG071995, R01AG070193, T32AG000266-23, R01AG061879, P01AG066591 and 1S10 OD016281. Different help got here from the Hevolution Basis, American Federation of Getting old Analysis, the Larry L. Hillblom Basis and the CatalystX award from Alex and Bob Griswold
