Glucose facilitates Aβ oligomerization and tau phosphorylation in C. elegans model of Alzheimer’s disease
AbstractFormation of Aβ plaques from peptide oligomers and development of neurofibrillary tangles from hyperphosphorylated tau are hallmarks of Alzheimer’s disease (AD). These markers of AD severity are further associated with impaired glucose metabolism. However, the exact role of glucose metabolism on disease progression has not been elucidated. In this study, the effects of glucose on Aβ and tau-mediated toxicity are investigated using a C. elegans model system. We find that addition of glucose or 2-deoxy-d-glucose (2DOG) to the growth medium delayed Aβ-associated paralysis, though it was unable to restore previously impaired acetylcholine neurotransmission in pre-existing Aβ-mediated pathology. Glucose also inhibited egg laying and hatching in the worms that express Aβ. The harmful effects of glucose were associated with an increase in toxic Aβ oligomers. Increased phosphorylation of tau is associated with formation of neurofibrillary tangles (NFTs) and increased severity of AD, but O-β-GlcNAcylation can inhibit phosphorylation of adjacent phosphorylation sites. We reasoned that high glucose levels might induce tau O-β-GlcNAcylation, thereby protecting against tau phosphorylation. Contrary to our expectation, glucose increased tau phosphorylation but not O-β-GlcNAcylation. Increasing O-β-GlcNAcylation, either with Thiamet-G (TMG) or by suppressing the O-GlcNAcase (oga-1) gene does interfere with and therefore reduce tau phosphorylation. Furthermore, reducing O-β-GlcNAcylation by suppressing O-GlcNAc transferase (ogt-1) gene causes an increase in tau phosphorylation. These results suggest that protective O-β-GlcNAcylation is not induced by glucose. Instead, as with vertebrates, we demonstrate that high levels of glucose exacerbate disease progression by promoting Aβ aggregation and tau hyperphosphorylation, resulting in disease symptoms of increased severity. The effects of glucose cannot be effectively managed by manipulating O-β-GlcNAcylation in the tau models of AD in C. elegans. Our observations suggest that glucose enrichment is unlikely to be an appropriate therapy to minimize AD progression.
