Differential Effects of 24-hydroxycholesterol and 27-hydroxycholesterol on Beta-amyloid Precursor Protein Levels and Processing in Human Neuroblastoma SH-SY5Y Cells

Overview

Journal Mol Neurodegener

Publisher Biomed Central

Specialties Molecular Biology
Neurology

Date 2009 Jan 8

PMID 19126211

Citations 51

Authors

Jaya Rp Prasanthi

Amber Huls

Sarah Thomasson

Alex Thompson

Eric Schommer

Othman Ghribi

Affiliations

Soon will be listed here.

Abstract

Background: Activation of the liver x receptors (LXRs) by exogenous ligands stimulates the degradation of beta-amyloid 1-42 (Abeta42), a peptide that plays a central role in the pathogenesis of Alzheimer's disease (AD). The oxidized cholesterol products (oxysterols), 24-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), are endogenous activators of LXRs. However, the mechanisms by which these oxysterols may modulate Abeta42 levels are not well known.

Results: We determined the effect of 24-OHC and/or 27-OHC on Abeta generation in SH-SY5Y cells. We found that while 27-OHC increases levels of Abeta42, 24-OHC did not affect levels of this peptide. Increased Abeta42 levels with 27-OHC are associated with increased levels of beta-amyloid precursor protein (APP) as well as beta-secretase (BACE1), the enzyme that cleaves APP to yield Abeta. Unchanged Abeta42 levels with 24-OHC are associated with increased levels of sAPPalpha, suggesting that 24-OHC favors the processing of APP to the non-amyloidogenic pathway. Interestingly, 24-OHC, but not 27-OHC, increases levels of the ATP-binding cassette transporters, ABCA1 and ABCG1, which regulate cholesterol transport within and between cells.

Conclusion: These results suggest that cholesterol metabolites are linked to Abeta42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of Abeta42 by upregulating APP and BACE1. Regulation of 24-OHC: 27-OHC ratio could be an important strategy in controlling Abeta42 levels in AD.

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References

Burns M, Vardanian L, Pajoohesh-Ganji A, Wang L, Cooper M, Harris D . The effects of ABCA1 on cholesterol efflux and Abeta levels in vitro and in vivo. J Neurochem. 2006; 98(3):792-800. DOI: 10.1111/j.1471-4159.2006.03925.x. View

Woodruff-Pak D, Agelan A, Del Valle L . A rabbit model of Alzheimer's disease: valid at neuropathological, cognitive, and therapeutic levels. J Alzheimers Dis. 2007; 11(3):371-83. DOI: 10.3233/jad-2007-11313. View

Ghribi O, Larsen B, Schrag M, Herman M . High cholesterol content in neurons increases BACE, beta-amyloid, and phosphorylated tau levels in rabbit hippocampus. Exp Neurol. 2006; 200(2):460-7. DOI: 10.1016/j.expneurol.2006.03.019. View

Vassar R, Bennett B, Kahn S, Mendiaz E, Denis P, Teplow D . Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999; 286(5440):735-41. DOI: 10.1126/science.286.5440.735. View

Chroni A, Kan H, Shkodrani A, Liu T, Zannis V . Deletions of helices 2 and 3 of human apoA-I are associated with severe dyslipidemia following adenovirus-mediated gene transfer in apoA-I-deficient mice. Biochemistry. 2005; 44(10):4108-17. DOI: 10.1021/bi047998l. View

Lange Y, Ye J, Rigney M, Steck T . Regulation of endoplasmic reticulum cholesterol by plasma membrane cholesterol. J Lipid Res. 1999; 40(12):2264-70. View

Anstey K, Lipnicki D, Low L . Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis. Am J Geriatr Psychiatry. 2008; 16(5):343-54. DOI: 10.1097/JGP.0b013e31816b72d4. View

Vassar R . BACE1: the beta-secretase enzyme in Alzheimer's disease. J Mol Neurosci. 2004; 23(1-2):105-14. DOI: 10.1385/JMN:23:1-2:105. View

Papassotiropoulos A, Lutjohann D, Bagli M, Locatelli S, Jessen F, Rao M . Plasma 24S-hydroxycholesterol: a peripheral indicator of neuronal degeneration and potential state marker for Alzheimer's disease. Neuroreport. 2000; 11(9):1959-62. DOI: 10.1097/00001756-200006260-00030. View

10.

Koldamova R, Staufenbiel M, Lefterov I . Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem. 2005; 280(52):43224-35. DOI: 10.1074/jbc.M504513200. View

11.

Famer D, Meaney S, Mousavi M, Nordberg A, Bjorkhem I, Crisby M . Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the alpha-secretase pathway. Biochem Biophys Res Commun. 2007; 359(1):46-50. DOI: 10.1016/j.bbrc.2007.05.033. View

12.

Brown 3rd J, Theisler C, Silberman S, Magnuson D, Gottardi-Littell N, Lee J . Differential expression of cholesterol hydroxylases in Alzheimer's disease. J Biol Chem. 2004; 279(33):34674-81. DOI: 10.1074/jbc.M402324200. View

13.

Papassotiropoulos A, Streffer J, Tsolaki M, Schmid S, Thal D, Nicosia F . Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol. 2003; 60(1):29-35. DOI: 10.1001/archneur.60.1.29. View

14.

Haass C, Selkoe D . Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell. 1993; 75(6):1039-42. DOI: 10.1016/0092-8674(93)90312-e. View

15.

Lutjohann D, Papassotiropoulos A, Bjorkhem I, Locatelli S, Bagli M, Oehring R . Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res. 2000; 41(2):195-8. View

16.

Lutjohann D, Breuer O, Ahlborg G, Nennesmo I, Siden A, Diczfalusy U . Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A. 1996; 93(18):9799-804. PMC: 38509. DOI: 10.1073/pnas.93.18.9799. View

17.

Sharma S, Prasanthi R P J, Schommer E, Feist G, Ghribi O . Hypercholesterolemia-induced Abeta accumulation in rabbit brain is associated with alteration in IGF-1 signaling. Neurobiol Dis. 2008; 32(3):426-32. PMC: 2658815. DOI: 10.1016/j.nbd.2008.08.002. View

18.

Heverin M, Bogdanovic N, Lutjohann D, Bayer T, Pikuleva I, Bretillon L . Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease. J Lipid Res. 2003; 45(1):186-93. DOI: 10.1194/jlr.M300320-JLR200. View

19.

Jiang Q, Lee C, Mandrekar S, Wilkinson B, Cramer P, Zelcer N . ApoE promotes the proteolytic degradation of Abeta. Neuron. 2008; 58(5):681-93. PMC: 2493297. DOI: 10.1016/j.neuron.2008.04.010. View

20.

Abildayeva K, Jansen P, Hirsch-Reinshagen V, Bloks V, Bakker A, Ramaekers F . 24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux. J Biol Chem. 2006; 281(18):12799-808. DOI: 10.1074/jbc.M601019200. View