Adaptation of neuronal cells to chronic oxidative stress is associated with altered cholesterol and sphingolipid homeostasis and lysosomal function

Abstract

Chronic oxidative stress has been causally linked to several neurodegenerative disorders. As sensitivity for oxidative stress greatly differs between brain regions and neuronal cell types, specific cellular mechanisms of adaptation to chronic oxidative stress should exist. Our objective was to identify molecular mechanisms of adaptation of neuronal cells after applying chronic sublethal oxidative stress. We demonstrate that cells resistant to oxidative stress exhibit altered cholesterol and sphingomyelin metabolisms. Stress‐resistant cells showed reduced levels of molecules involved in cholesterol trafficking and intracellular accumulation of cholesterol, cholesterol precursors, and metabolites. Moreover, stress‐resistant cells exhibited reduced SMase activity. The altered lipid metabolism was associated with enhanced autophagy. Treatment of stress‐resistant cells with neutral SMase reversed the stress‐resistant phenotype, whereas it could be mimicked by treatment of neuronal cells with a specific inhibitor of neutral SMase. Analysis of hippocampal and cerebellar tissue of mouse brains revealed that the obtained cell culture data reflect the in vivo situation. Stress‐resistant cells in vitro showed similar features as the less vulnerable cerebellum in mice, whereas stress‐sensitive cells resembled the highly sensitive hippocampal area. These findings suggest an important role of the cell type‐specific lipid profile for differential vulnerabilities of different brain areas toward chronic oxidative stress.

Sphingolipid Storage Affects Autophagic Metabolism of the Amyloid Precursor Protein and Promotes Aβ Generation

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DNA damage in the oligodendrocyte lineage and its role in brain aging

“…This presents a significant problem for the OL since, to make the lipid-rich myelin layers during differentiation and maintain them during adult life, a large amount of cholesterol is required and cholesterol synthesis is an energy intensive process. While the OLs synthesize cholesterol de novo via 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) mediated metabolism (Saher et al, 2005), the transfer of cholesterol from astrocyte to oligodendrocyte also contributes significantly, especially in aging when the levels of HMG-coA drop (Clement et al, 2009; Thelen et al, 2006). On top of the metabolic demands created by the production of cholesterol esters, the OLs also play a major role in providing trophic support for the neurons they interact with.…”

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