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

Abstract

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.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.

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

“…Mitochondrial protein O-GlcNAcylation plays an important role in regulating cellular function; the destruction of O-GlcNAcylation homeostasis is involved in the pathogenesis of chronic diseases such as diabetes [43,72,73], neurodegenerative diseases [74,75], tumors [28,76,77] and CVDs [14,26,44]. Insulin resistance and diabetic CVDs are promoted by O-GlcNAcylation through an increase in the imbalance of multiple signaling pathways at the transcriptional, translational and posttranslational levels.…”

Mitochondria in Alzheimer’s Disease Pathogenesis

“…Studies have also explored the effects of reduced O-GlcNAcylation, a posttranslational modification that regulates human nuclear, cytoplasmic, and mitochondrial proteins in AD [150]. O-GlcNAcylation involves the attachment of a single N-acetylglucosamine sugar to specific serine or threonine residues on over 9000 proteins of nuclear, cytosolic, and mitochondrial origin [151].…”