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Italian Journal of Pediatrics
Published in: Italian Journal of Pediatrics 1/2016

Open Access 01-12-2016 | Research

Liver X receptor-β improves autism symptoms via downregulation of β-amyloid expression in cortical neurons

Authors: Ji-Xiang Zhang, Jun Zhang, Ye Li

Published in: Italian Journal of Pediatrics | Issue 1/2016

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Abstract

Background

We study the effect of liver X receptor β (LXRβ) on β-amyloid (Aβ) peptide generation and autism behaviors by conducting an animal experiment.

Methods

In autistic mice treated with LXRβ agonist T0901317, enzyme linked immunosorbent assay was used to measure Aβ in brain tissue homogenates. Western blot was used to detect Aβ precursors, Aβ degradation and secretase enzymes, and expression of autophagy-related proteins and Ras/Raf/Erkl/2 signaling pathway proteins in brain tissue. Changes in autism spectrum disorder syndromes of the BTBR mice were compared before and after T0901317 treatment.

Results

Compared with the control group, autistic mice treated with LXRβ agonist T0901317 showed significantly lower Aβ level in brain tissue (P < 0.05), significantly higher Aβ degradation enzyme (NEP, IDE proteins) levels (all P < 0.05), significantly lower Aβ secretase enzyme BACE1 protein level (P < 0.05), and significantly lower Ras, P-C-Raf, C-Raf, P-Mekl/2, P-Erkl/2 protein levels (all P < 0.05). BTBR mice treated with T0901317 showed improvements in repetitive stereotyped behavior, inactivity, wall-facing standing time, self-combing time and center stay time, stayed longer in platform quadrant, and crossed the platform more frequently (all P < 0.05).

Conclusions

LXRβ could potentially reduce brain Aβ generation by inhibiting Aβ production and promoting Aβ degradation, thereby increasing the expression of autophagy-related proteins, reducing Ras/Raf/Erkl/2 signaling pathway proteins, and improving autism behaviors.
Literature
1.
2.
Tchaconas A, Adesman A. Autism spectrum disorders: a pediatric overview and update. Curr Opin Pediatr. 2013;25(1):130–44.CrossRefPubMed
3.
Li N, Chen G, Song X, Du W, Zheng X. Prevalence of autism-caused disability among Chinese children: a national population-based survey. Epilepsy Behav. 2011;22(4):786–9.CrossRefPubMed
4.
Ha S, Sohn IJ, Kim N, Sim HJ, Cheon KA. Characteristics of Brains in Autism Spectrum Disorder: Structure, Function and Connectivity across the Lifespan. Exp Neurobiol. 2015;24(4):273–84.CrossRefPubMedPubMedCentral
5.
Heyvaert M, Saenen L, Campbell JM, Maes B, Onghena P. Efficacy of behavioral interventions for reducing problem behavior in persons with autism: an updated quantitative synthesis of single-subject research. Res Dev Disabil. 2014;35(10):2463–76.CrossRefPubMed
6.
Durkin MS, Elsabbagh M, Barbaro J, Gladstone M, Happe F, Hoekstra RA, et al. Autism screening and diagnosis in low resource settings: Challenges and opportunities to enhance research and services worldwide. Autism Res. 2015;8(5):473–6.CrossRefPubMed
7.
Matelski L, Van de Water J. Risk factors in autism: Thinking outside the brain. J Autoimmun. 2015;67:1–7
8.
Theofilopoulos S, Arenas E. Liver X receptors and cholesterol metabolism: role in ventral midbrain development and neurodegeneration. F1000Prime Rep. 2015;7:37.CrossRefPubMedPubMedCentral
9.
Sodhi RK, Singh N. Liver X receptors: emerging therapeutic targets for Alzheimer’s disease. Pharmacol Res. 2013;72:45–51.CrossRefPubMed
10.
Baranowski M. Biological role of liver X receptors. J Physiol Pharmacol. 2008;59 Suppl 7:31–55.PubMed
11.
Fan X, Kim HJ, Bouton D, Warner M, Gustafsson JA. Expression of liver X receptor beta is essential for formation of superficial cortical layers and migration of later-born neurons. Proc Natl Acad Sci U S A. 2008;105(36):13445–50.CrossRefPubMedPubMedCentral
12.
Warner M, Gustafsson JA. Estrogen receptor beta and Liver X receptor beta: biology and therapeutic potential in CNS diseases. Mol Psychiatry. 2015;20(1):18–22.CrossRefPubMed
13.
Barry DS, Pakan JM, McDermott KW. Radial glial cells: key organisers in CNS development. Int J Biochem Cell Biol. 2014;46:76–9.CrossRefPubMed
14.
Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, et al. The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer’s disease. J Biol Chem. 2005;280(6):4079–88.CrossRefPubMed
15.
Sun X, Chen WD, Wang YD. beta-Amyloid: the key peptide in the pathogenesis of Alzheimer’s disease. Front Pharmacol. 2015;6:221.PubMedPubMedCentral
16.
Korsak M, Kozyreva T. Beta Amyloid Hallmarks: From Intrinsically Disordered Proteins to Alzheimer’s Disease. Adv Exp Med Biol. 2015;870:401–21.CrossRefPubMed
17.
Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007;8(2):101–12.CrossRefPubMed
18.
Yu J, Ryan DG, Getsios S, Oliveira-Fernandes M, Fatima A, Lavker RM. MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia. Proc Natl Acad Sci U S A. 2008;105(49):19300–5.CrossRefPubMedPubMedCentral
19.
Yu J, Peng H, Ruan Q, Fatima A, Getsios S, Lavker RM. MicroRNA-205 promotes keratinocyte migration via the lipid phosphatase SHIP2. FASEB J. 2010;24(10):3950–9.CrossRefPubMedPubMedCentral
20.
Kelley AE. Measurement of rodent stereotyped behavior. Curr Protoc Neurosci. 2001;Chapter 8:Unit 8.PubMed
21.
Tan XJ, Fan XT, Kim HJ, Butler R, Webb P, Warner M, et al. Liver X receptor beta and thyroid hormone receptor alpha in brain cortical layering. Proc Natl Acad Sci U S A. 2010;107(27):12305–10.CrossRefPubMedPubMedCentral
22.
Infante J, Rodriguez-Rodriguez E, Mateo I, Llorca J, Vazquez-Higuera JL, Berciano J, et al. Gene-gene interaction between heme oxygenase-1 and liver X receptor-beta and Alzheimer’s disease risk. Neurobiol Aging. 2010;31(4):710–4.CrossRefPubMed
23.
Sacchetti P, Sousa KM, Hall AC, Liste I, Steffensen KR, Theofilopoulos S, et al. Liver X receptors and oxysterols promote ventral midbrain neurogenesis in vivo and in human embryonic stem cells. Cell Stem Cell. 2009;5(4):409–19.CrossRefPubMed
24.
Koldamova R, Lefterov I. Role of LXR and ABCA1 in the pathogenesis of Alzheimer’s disease - implications for a new therapeutic approach. Curr Alzheimer Res. 2007;4(2):171–8.CrossRefPubMed
25.
Fitz NF, Cronican A, Pham T, Fogg A, Fauq AH, Chapman R, et al. Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice. J Neurosci. 2010;30(20):6862–72.CrossRefPubMedPubMedCentral
26.
Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R. Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegener. 2007;2:20.CrossRefPubMedPubMedCentral
27.
Zhao Z, Xiang Z, Haroutunian V, Buxbaum JD, Stetka B, Pasinetti GM. Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer’s disease. Neurobiol Aging. 2007;28(6):824–30.CrossRefPubMed
28.
Wang S, Wang R, Chen L, Bennett DA, Dickson DW, Wang DS. Expression and functional profiling of neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme in prospectively studied elderly and Alzheimer’s brain. J Neurochem. 2010;115(1):47–57.CrossRefPubMedPubMedCentral
29.
Devi L, Ohno M. Effects of BACE1 haploinsufficiency on APP processing and Abeta concentrations in male and female 5XFAD Alzheimer mice at different disease stages. Neuroscience. 2015;307:128–37.CrossRefPubMed
30.
Sawamura N, Ko M, Yu W, Zou K, Hanada K, Suzuki T, et al. Modulation of amyloid precursor protein cleavage by cellular sphingolipids. J Biol Chem. 2004;279(12):11984–91.CrossRefPubMed
31.
Tamagno E, Guglielmotto M, Giliberto L, Vitali A, Borghi R, Autelli R, et al. JNK and ERK1/2 pathways have a dual opposite effect on the expression of BACE1. Neurobiol Aging. 2009;30(10):1563–73.CrossRefPubMed
32.
Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209–21.CrossRefPubMedPubMedCentral
33.
Davis S, Laroche S. Mitogen-activated protein kinase/extracellular regulated kinase signalling and memory stabilization: a review. Genes Brain Behav. 2006;5 Suppl 2:61–72.CrossRefPubMed
34.
Yang K, Sheikh AM, Malik M, Wen G, Zou H, Brown WT, et al. Upregulation of Ras/Raf/ERK1/2 signaling and ERK5 in the brain of autistic subjects. Genes Brain Behav. 2011;10(8):834–43.CrossRefPubMed
35.
Zou H, Yu Y, Sheikh AM, Malik M, Yang K, Wen G, et al. Association of upregulated Ras/Raf/ERK1/2 signaling with autism. Genes Brain Behav. 2011;10(5):615–24.CrossRefPubMed
36.
Murphy LO, Blenis J. MAPK signal specificity: the right place at the right time. Trends Biochem Sci. 2006;31(5):268–75.CrossRefPubMed
37.
Yin A, Qiu Y, Jia B, Song T, Yu Y, Alberts I, et al. The developmental pattern of the RAS/RAF/Erk1/2 pathway in the BTBR autism mouse model. Int J Dev Neurosci. 2014;39:2–8.CrossRefPubMed
Metadata
Title
Liver X receptor-β improves autism symptoms via downregulation of β-amyloid expression in cortical neurons
Authors
Ji-Xiang Zhang
Jun Zhang
Ye Li
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Italian Journal of Pediatrics / Issue 1/2016
Electronic ISSN: 1824-7288
DOI
https://doi.org/10.1186/s13052-016-0249-4

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