Abstract
Alterations 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.
Highlights
Alzheimer’s disease (AD) is strongly associated with elevated circulating cholesterol during mid-life [1,2,3,4,5]
S100A8 expression was analyzed in the hippocampus of wild-type mice (WT) fed with high-fat diet (HFD) (WT-HFD) compared to a normal diet (WT-normal chow diet (ND)) through immunohistochemical analysis
Consistent with the accumulation of S100A8 seen in AD mouse models [23], cresyl violet staining revealed no overlap between the corpora amylacea (CA) and the S100A8 aggregates (Fig. 1A, insets b vs. c)
Summary
Alzheimer’s disease (AD) is strongly associated with elevated circulating cholesterol during mid-life [1,2,3,4,5]. Cholesterol itself does not cross the blood–brain barrier (BBB), posing the question of how plasma hypercholesterolemia is Extended author information available on the last page of the article linked to the risk of developing AD. Its side-chain oxidized metabolite, 27-hydroxycholesterol (27OH), is able to traverse the BBB and correlates directly to circulating cholesterol levels in plasma in humans [13]. We have reported alterations in cognition observed in mice on a high-fat diet (HFD) [14] as well as in the chronically high 27-OH transgenic mice, CYP27A1 overexpressor (CYP27Tg) [15], suggesting that 27-OH may be mediated some of the deleterious effects of high peripheric cholesterol in the brain [16]. We have shown that 27-OH affects the levels of the activity-regulated cytoskeleton-associated protein (Arc), a protein involved in long-term consolidation of memory [16]
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