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.
Keywords: O-GlcNAcylation; glucose metabolism; human cortical neurons; mitochondrial dysfunction; sporadic Alzheimer's disease.
© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.