S3-03-01: O-glycosylation regulates phosphorylation of tau:A novel mechanism leading to neurofibrillarydegeneration in Alzheimer disease

Abstract

Neurofibrillary degeneration plays a pivotal role in the pathogenesis of Alzheimer disease (AD) and other related tauopathies and is directly associated with dementia symptoms of the patients. It is characterized by abnormal hyperphosphorylation and aggregation of tau protein as neurofibrillary tangles in the affected neurons. We have found that human brain tau is post–translationally modified by β–N–acetyl–glucosamine (GlcNAc) in addition to phosphorylation. This novel type of O–glycosylation is called O–GlcNAcylation and regulates phosphorylation of tau inversely. In differentiated PC12 cells and in metabolically active rat brain slices, elevation of O–GlcNAcylation induced dephosphorylation of tau at multiple phosphorylation sites, whereas reduction of O–GlcNAcylation resulted in hyperphosphorylation of tau. Reduction of glucose uptake/metabolism by culturing the cells in medium with low glucose concentration or by specific inhibitors resulted in decreased O–GlcNAcylation and consequently hyperphosphorylation of tau. Fasting–induced decrease in glucose uptake/metabolism caused downregulation of tau O–GlcNAcylation and upregulation of tau phosphorylation in a site–specific manner 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 tau O–GlcNAcylation was decreased in AD brain, and this decrease was correlated negatively to the level of tau phosphorylation at multiple abnormal phosphorylation sites. On the basis of these findings, we propose a novel mechanism whereby the impaired brain glucose uptake/metabolism, which causes deficient tau O–GlcNAcylation, contributes to Alzheimer neurofibrillary degeneration by facilitating abnormal hyperphosphorylation of tau.