Investigating the role of neuroglobin in cholesterol metabolism: a spotlight on brain-derived cells

Background: Cholesterol is a crucial determinant of membrane structure, signaling, and synaptic function in the central nervous system, where its homeostasis is tightly controlled to support neuronal viability and plasticity to prevent neurodegeneration. Altered brain cholesterol metabolism is increasingly recognized as a shared feature of several neurological disorders as well as age-associated cognitive decline. In parallel, neuroglobin has emerged as an endogenous neuroprotective protein in the brain, where its overexpression limits oxidative damage, mitochondrial dysfunction, and cell death in experimental models of hypoxia, ischemia, and proteinopathy. Despite extensive research on cholesterol turnover in the brain and on neuroglobin-mediated cytoprotection, the functional relationship between these two processes remains largely unexplored. The purpose of this study was to investigate whether neuroglobin modulates the cholesterol regulatory network in brain-derived cells and whether it affects the astrocyte-dependent cholesterol supply to neurons. Methods: Human neuronal-like (SH-SY5Y) and astrocyte-like (U373) cell lines overexpressing neuroglobin were used to examine the effects of globin on key regulators of cholesterol synthesis, uptake, intracellular trafficking, and storage, as well as on susceptibility to oxidative stress. Western blot and immunofluorescence analyses were performed. Results: The results demonstrate that neuroglobin is seemingly associated with changes in cholesterol homeostasis in a cell type-specific manner, modulating the expression of different proteins involved in cholesterol metabolism and promoting cellular cholesterol accumulation without affecting the cross-talk between astrocytes and neurons. Conclusions: Overall, these findings suggest that NGB can be a novel modulator of cholesterol homeostasis in brain-derived cells, extending its role beyond the mitigation of oxidative stress in neurons to include defense against metabolic dysregulation.