Hypercholesterolemia and 27-Hydroxycholesterol Increase S100A8 and RAGE Expression in the Brain: a Link Between Cholesterol, Alarmins, and Neurodegeneration

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.Open access funding provided by Karolinska Institute. This research was supported by the following Swedish foundations: Swedish Brain Power, the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, Strategic Neuroscience Program, Margaretha af Ugglas Foundation, Gun och Bertil Stohnes Stiftelse, Karolinska Institutet fund for geriatric research, Stiftelsen Gamla Tjänarinnor, Demensfonden,Lindhés Advokatbyrå, Hjärnfonden, and Alzheimerfonden. R. L.-V. was fnancially supported by Mexico’s National Council for Science and Technology (CONACYT) CVU, 209252, and by Olle Enqvist Foundation grant no. 2014/778. Ramon Areces Foundation, Spain, supported E. P., EMBO Long-Term Fellowship (ALTF 696–2013), the SSMF postdoctoral fellowship, and Juan de la Cierva-Incorporación. (IJCI-2016–27,658) supported P. M.-S

Reading Motivation Scale For Elementary Education Students: Construction And Validation [escala De Motivação Para A Leitura Para Estudantes Do Ensino Fundamental: Construção E Validação]

The purpose of this study was to describe the steps of constructing and validating a reading motivation scale for elementary education students as well as to present a preliminary analysis of its psychometric properties. The sample was composed of 253 Brazilian students, from 3rd to 5th grades, of Primary Education Public Schools. The exploratory factorial analyses identified four factors: Extrinsic Autonomous Motivation for Reading, Demotivation for Reading, Extrinsic Controlled Motivation for Reading and Intrinsic Motivation for Reading which explained 42.71% of the total variance. The internal consistency of the scale, estimated by Cronbach alpha, was.83 and ranged from.80 to.87 for the four factors. The scale has evidence of validity and reliability for its use in school context