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

Abstract Introduction Sporadic 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. Methods Human cortical neurons were generated from pluripotent stem cells (PSCs) and treated with glucose reduction media. Results We 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. Discussion Our 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. HIGHLIGHTS Lowering 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.