title: 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.
authors.affiliation: Institute of Experimental Pharmacology & Toxicology Slovak Academy of Sciences, Bratislava, Slovak Republic. lucia_rackova@hotmail.com
authors.forename: Lucia
authors.initials: L
authors.lastname: Račková
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D002784:Cholesterol / Q000494:pharmacology*; D004265:DNA Helicases / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D008565:Membrane Proteins; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D002784:Cholesterol; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C518330:RUVBL2 protein, mouse
keywords: Cholesterol; Lipid rafts; Microglia; Oxidative stress; Phagocytosis