Cholesterol load of microglia: Contribution of membrane architecture changes to neurotoxic power?

Abstract

Considerable evidence provides a link between hypercholesterolemia and ageing-related neurodegenerative diseases. The present study was aimed to provide a complex view on the effects caused by cholesterol- and cholesterol 5α,6α-epoxide-load in microglia, with particular emphasize put on membrane proteins.Prolonged application of oxysterol significantly enhanced LPS-stimulated association of cytosolic NADPH-oxidase factor p47[phox] with detergent-resistant microdomains (DRMs) in BV-2 cells. Although the treatment with both sterols does not influence the portion of CD36 receptor in DRMs, its apparent surface-cellular expression was altered. Even though sterol-treatment potentiated oxidant production by microglia, as well as their phagocytosis, these effects, however, appeared to be independent of cholesterol profusion in the membrane. In addition, oxysterol-treatment resulted in a loss of DRMs-associated activity of 26S proteasome, the protease critically regulating both protein homeostasis and immune signaling in microglia. Oxysterol relatively ameliorated cytotoxic effects of inflammed microglia on co-cultured PC12 cells.The outcomes of this study suggest that cholesterol and cholesterol oxides can differentially modulate microglia resulting either in impairment of their immune functionalities or enhanced neurotoxic power. Moreover, these findings shed light on possible complexity of this effect, produced by simultaneous affection of the levels, distribution and function of the critical proteins within microglial membrane compartments.