O2-05-08: Protein O-Glcnacylation: A novel mechanism involved in Alzheimer's disease

Abstract

Neurofibrillary degeneration plays a pivotal role in the pathogenesis of Alzheimer disease (AD) and correlates directly with dementia of affected individuals. However, the molecular mechanism(s) leading to neurofibrillary degeneration is not well understood. Microtubule-associated protein tau and neurofilaments are the key proteins involved in neurofibrillary degeneration and are post-translationally modified by both O-GlcNAcylation (a unique type of O-glycosylation of protein with β-N-acetyl-glucosamine, GlcNAc) and phosphorylation. The role of O-GlcNAcylation in phosphorylation of tau and neurofilaments were studied in vitro, in cultured cells, in metabolically active rat brain slices, and in vivo. We found that O-GlcNAcylation of tau and neurofilaments regulates their phosphorylation inversely. In cell cultures and in metabolically active rat brain slices, elevation of O-GlcNAcylation induced decreased phosphorylation of tau and neurofilaments at multiple phosphorylation sites, whereas reduction of O-GlcNAcylation resulted in hyperphosphorylation of these proteins. In vivo, fasting-induced decrease in glucose uptake/metabolism caused down-regulation of O-GlcNAcylation and upregulation of phosphorylation of tau and neurofilaments in the mouse brain. Hippocampus was found to be more vulnerable than cerebral cortex to the fasting-induced alteration of tau O-GlcNAcylation and phosphorylation, which is consistent with the differential susceptibility of various brain regions in AD. Re-feeding of the mice reversed the dysregulation of both O-GlcNAcylation and phosphorylation of tau. More importantly, the level of O-GlcNAcylation of tau and neurofilaments was decreased in AD brain, and this decrease was correlated negatively to the level of phosphorylation of these two proteins. The major glucose transporters (GLUTs) responsible for glucose uptake into neurons from blood stream, GLUT1 and GLUT3, were decreased in AD brain. This decrease correlated to the decrease in protein O-GlcNAcylation, to the hyperphosphorylation of tau, and to the density of neurofibrillary tangles in human brains. On the basis of our findings, we propose a novel mechanism by which the impaired brain glucose uptake/metabolism causes a decrease in tau O-GlcNAcylation, leading to Alzheimer neurofibrillary degeneration by facilitating abnormal hyperphosphorylation of tau and neurofilaments.