Abstract
AbstractAlterations in cholesterol metabolism in the brain have a major role in the physiology of Alzheimer’s disease (AD). Oxysterols are cholesterol metabolites with multiple implications in memory functions and in neurodegeneration. Previous studies have shown detrimental effects of cholesterol metabolites in neurons, but its effect in glial cells is unknown. We used a high-fat/high-cholesterol diet in mice to study the effects of hypercholesterolemia over the alarmin S100A8 cascade in the hippocampus. Using CYP27Tg, a transgenic mouse model, we show that the hypercholesterolemia influence on the brain is mediated by the excess of 27-hydroxycholesterol (27-OH), a cholesterol metabolite. We also employed an acute model of 27-OH intraventricular injection in the brain to study RAGE and S100A8 response. We used primary cultures of neurons and astrocytes to study the effect of high levels of 27-OH over the S100A8 alarmin cascade. We report that a high-fat/high-cholesterol diet leads to an increase in S100A8 production in the brain. In CYP27Tg, we report an increase of S100A8 and its receptor RAGE in the hippocampus under elevated 27-OH in the brain. Using siRNA, we found that 27-OH upregulation of RAGE in astrocytes and neurons is mediated by the nuclear receptor RXRγ. Silencing RXRγ in neurons prevented 27-OH-mediated upregulation of RAGE. These results show that S100A8 alarmin and RAGE respond to high levels of 27-OH in the brain in both neurons and astrocytes through RXRγ. Our study supports the notion that 27-OH mediates detrimental effects of hypercholesterolemia to the brain via alarmin signaling.
Funder
Swedish Brain Power
Stiftelsen för Strategisk Forskning
Margaretha af Ugglas Stiftelse
Gun och Bertil Stohnes Stiftelse
Karolinska Institutet
Stiftelsen för Gamla Tjänarinnor
Demensförbundet
Lindhés Advokatbyra
Hjärnfonden
Alzheimerfonden
CONACYT
Stiftelsen Olle Engkvist Byggmästare
Fundación Ramón Areces
EMBO
Karolinska Institute
Publisher
Springer Science and Business Media LLC
Subject
Neuroscience (miscellaneous),Cellular and Molecular Neuroscience,Neurology
Cited by
25 articles.
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