Background: Aging is a complex process involving both genetic and environmental factors. Aging and neurodegeneration share some of these influential risk factors, with aging itself being the most robust risk factor for neurodegeneration. Several recent studies have demonstrated that aberrant accumulation of glycogen in neurons can lead to premature aging and neurodegeneration in both flies and mice. Moreover, granular glycogen bodies have also been observed in postmortem cerebral cortex sections of Alzheimer's disease (AD) and dementia patients. Whether glycogen accumulation in the brain occurs in all neurodegenerative diseases and contributes to disease pathogenesis remains unclear. Thus, my main objective is to determine whether accumulation of glycogen within the brain leads to premature brain aging and neurodegeneration.
Methods: To study the impact of increased levels of glycogen in brain aging and neurodegeneration two approaches are used. First, transgenes encoding constitutively active and catalytically dead versions of human muscle glycogen synthase (hMGS) were expressed within neurons of Drosophila melanogaster and an amyloglucosidase-based assay was used to measure glycogen levels from fly brains. The effect of glycogen accumulation was determined by measuring sensitivity to oxidative stress. Alternatively, the glycogen concentration in the heads of AD model flies will be manipulated using pharmacological approaches and its effects will be determined by measuring sensitivity to oxidative stress, lifespan and cognition using an olfactory learning assay.
Results: Flies overexpressing a constitutively active hMGS showed higher sensitivity to oxidative stress compared to control flies.
Conclusion: This study will show us whether glycogen accumulation within the brain is a pathogenic feature of neurodegeneration in AD and whether neurodegenerative phenotypes of AD can be ameliorated by reducing glycogen levels.