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GLUT inhibitor WZB117 induces cytotoxicity with increased production of amyloid-beta peptide in SH-SY5Y cells preventable by beta-hydroxybutyrate: implications in Alzheimer's disease. | LitMetric

AI Article Synopsis

  • - Researchers tested the glucose transporter inhibitor WZB117 on human neuroblastoma cells (SH-SY5Y) to investigate its impact on Alzheimer's-related processes like amyloid-beta accumulation and mitochondrial dysfunction.
  • - Exposure to WZB117 led to negative effects including increased oxidative stress, mitochondrial dysfunction, and cell death, along with raised levels of BACE 1 and amyloid-beta peptide.
  • - Co-treatment with β-hydroxybutyrate successfully mitigated the harmful effects of WZB117, suggesting potential therapeutic avenues, though cyclosporine A did not prevent cell death.

Article Abstract

Background: Inhibitors of glucose transporters are being explored as potential anti-cancer drugs. Decreased cerebral glucose utilization with reduced levels of several glucose transporters is also an important pathogenic signature of neurodegeneration of Alzheimer's disease, but its exact role in the pathogenesis of this disease is not established. We explored in an experimental model if inhibitors of glucose transporters could lead to altered amyloid-beta homeostasis, mitochondrial dysfunction, and neuronal death, which are relevant in the pathogenesis of Alzheimer's disease.

Methods: SH-SY5Y cells (human neuroblastoma cell line) were exposed to an inhibitor (WZB117) of several types of glucose transporters. We examined the effects of glucose hypometabolism on SH-SY5Y cells in terms of mitochondrial functions, production of reactive oxygen species, amyloid-beta homeostasis, and neural cell death. The effect of β-hydroxybutyrate in ameliorating the effects of WZB117 on SH-SY5Y cells was also examined.

Results: We observed that exposure of SH-SY5Y cells to WZB117 caused mitochondrial dysfunction, increased production of reactive oxygen species, loss of cell viability, increased expression of BACE 1, and intracellular accumulation of amyloid β peptide (Aβ42). All the effects of WZB117 could be markedly prevented by co-treatment with β-hydroxybutyrate. Cyclosporine A, a blocker of mitochondrial permeability transition pore (mPTP) activation, could not prevent cell death caused by WZB117.

Conclusion: Results in this neuroblastoma model have implications for the pathogenesis of Alzheimer's disease and warrant further explorations of WZB117 in primary cultures of neurons and experimental animal models.

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Source
http://dx.doi.org/10.1007/s43440-023-00466-4DOI Listing

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