Low glucose induced Alzheimer's disease-like biochemical changes in human induced pluripotent stem cell-derived neurons is due to dysregulated O-GlcNAcylation

IntroductionSporadic Alzheimer's disease (sAD) is the leading type of dementia. Brain glucose hypometabolism, along with decreased O-GlcNAcylation levels, occurs before the onset of symptoms and correlates with pathogenesis. Heretofore, the mechanisms involved and the roles of O-GlcNAcylation in sAD pathology largely remain unknown due to a lack of human models of sAD. MethodsHuman cortical neurons were generated from pluripotent stem cells (PSCs) and treated with glucose reduction media. ResultsWe found a narrow window of glucose concentration that induces sAD-like phenotypes in PSC-derived neurons. With our model, we reveal that dysregulated O-GlcNAc, in part through mitochondrial dysfunction, causes the onset of sAD-like changes. We demonstrate the therapeutic potential of inhibiting O-GlcNAcase in alleviating AD-like biochemical changes. DiscussionOur results suggest that dysregulated O-GlcNAc might be a direct molecular link between hypometabolism and sAD-like alternations. Moreover, this model can be exploited to explore molecular processes and for drug development. HIGHLIGHTSLowering glucose to a critical level causes AD-like changes in cortical neurons.Defective neuronal structure and function were also recapitulated in current model.Dysregulated O-GlcNAcylation links impaired glucose metabolism to AD-like changes.Mitochondrial abnormalities correlate with O-GlcNAcylation and precede AD-like phenotype.Our model provides a platform to study sAD as a metabolic disease in human neurons.