Effect of sublethal copper overload on cholesterol de novo synthesis in undifferentiated neuronal cells

ZUBILLAGA, MARLENE; ROSA, D; ASTIZ, M.; TRICERRI, M. A.; ARNAL, N

ACS Omega

ACS

Lugar: Washington DC; Año: 2022

2470-1343

Despite copper (Cu) is an essential trace metal for cells, it can induce harmful effects as it participates in the Fenton reaction. Involuntary exposure to Cu overload is much common than expected and has been linked with neurodegeneration, particularly with Alzheimer’s disease (AD) evidenced by a positive correlation between free Cu in plasma and the severity of the disease. It has been suggested that Cu imbalance alters cholesterol (Chol) homeostasis and that high membrane Chol promotes the amyloidogenic processing of the amyloid precursor protein (APP) secreting the β-amyloid (Aβ) peptide. Despite the wide knowledge on the effects of Cu in mature brain metabolism, the consequence of its overload on immature neurons remains unknown. Therefore, we used an undifferentiated human neuroblastoma cell line (SH-SY5Y) to analyze the effect of sub-lethal concentrations of Cu on: 1- The de novo Chol synthesis and membrane distribution; 2- APP levels in cells and its distribution in membrane rafts; 3- The levels of Aβ in the culture medium. Our results demonstrated that Cu increases ROS and favors Chol de novo synthesis in both ROS-dependent and independent manner. Also, at least part of these effects was due to the activation of 3-hydroxy-3-methyl glutharyl CoA reductase (HMGCR). In addition, Cu increases Chol/PL ratio at the cellular membranes, specifically Chol content in membrane rafts. We found no changes in total APP cell levels, however, its presence in membrane rafts increases, with the consequent increase of Aβ in culture medium.