Low Glucose Induced Alzheimer’s Disease Phenotype in Induced Pluripotent Stem Cell‐Derived Neurons is Due to Decreased O‐GlcNAcylation
In: The FASEB Journal ; volume 36, issue S1 ; ISSN 0892-6638 1530-6860, 2022
academicJournal
Zugriff:
Sporadic Alzheimer’s disease (sAD) is the most common type of neurodegenerative disease. Recent studies show that detectable impairment of brain glucose metabolism occurs years before onset of AD symptoms, and the dysregulated O‐GlcNAc levels likely arisen from impaired glucose metabolism correlates with AD pathogenesis. So far, the mechanism of sAD and the role of OGN in AD pathology remained largely unknown due to a lack of human sAD model. We have established a human sAD model in which the pathological features are reproduced by glucose deficiency that better represents sAD as a metabolic disease. We generated human cortical neurons from human induced pluripotent stem cell and treated mature neuron with glucose reduction media to study the effect of low glucose on the degenerative status of neuron. Fluoro JADE C staining and cell viability assays reveals low glucose treatment at 2mM leads to dramatic increases of degeneration cell on day 3 and 5 of treatment and decreased cell viability on day 7. Interestingly, western blotting and immunofluorescent staining results demonstrate that long‐term low glucose treatment induces two major AD features in cortical neuron, including accumulation of abnormal hyperphosphorylated tau and increasing amyloid beta production. In addition, glucose deficiency also causes decreased neurite coverage, synapse loss, and neuron network activity disruption detected by immunofluorescent staining and multi‐electrode array electrophysiological analyses. Furthermore, we find that O‐GlcNAc levels are significantly reduced soon after low glucose treatment and last till the end of experiment. Artificially increasing O‐GlcNAc level by thiamet‐G (TMG) in low glucose treated neurons, rescues low glucose‐induced AD phenotypes. Moreover, our data show that O‐GlcNAc dysregulation results in mitochondrial dysfunction, which occurs before any other degenerative phenotype appeared, and may be one of the underlying mechanisms of sAD onset and pathogenesis. Taken together, we established a human sAD ...
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Low Glucose Induced Alzheimer’s Disease Phenotype in Induced Pluripotent Stem Cell‐Derived Neurons is Due to Decreased O‐GlcNAcylation
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Autor/in / Beteiligte Person: | Huang, Chia‐Wei ; Hart, Gerald |
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Zeitschrift: | The FASEB Journal ; volume 36, issue S1 ; ISSN 0892-6638 1530-6860, 2022 |
Veröffentlichung: | Wiley, 2022 |
Medientyp: | academicJournal |
DOI: | 10.1096/fasebj.2022.36.s1.r2271 |
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