title: Interactions of amyloid β peptide 1-40 and cerebrosterol.
abstract: Amyloid β peptides appear to play a role in physiological processes; however, they are also involved in the pathogenesis of Alzheimer disease. Their actions under normal conditions are probably mediated by soluble monomeric L-isoforms at low concentrations, perhaps via highly specific interactions. On the contrary, toxic effects of aggregated natural L-isoforms/synthetic D-isoforms on membranes are very similar, but synthetic reverse/random L: -isoforms without pronounced aggregation properties are not toxic. Our previous work reported interactions of non-aggregated/aggregated L-isoforms of amyloid β peptides 1-40/1-42 with racemic 24-hydroxycholesterol. In this study, stereospecificity in the interactions of natural 24(S)hydroxycholesterol (cerebrosterol) or synthetic 24(R)hydroxycholesterol with soluble fragment 1-40 was evaluated by means of an in vitro test based on increased vulnerability of the hemicholinium-3 sensitive high-affinity choline uptake system in rat hippocampal cholesterol-depleted synaptosomes to the actions of amyloid β; computational simulations were also performed. Our results suggest that: (1) 24(S)hydroxycholesterol interacts with L-peptide 1-40 but not with the reverse L-peptide 40-1, (2) 24(R)hydroxycholesterol does not interact with L-peptide 1-40 or reverse 40-1, and (3) both enantiomers can probably interact with D-peptide 1-40. Therefore, the binding of 24(S)hydroxycholesterol is not fully stereospecific and the interaction could not reflect a physiological mechanism. Data from the computational simulation indicate that the hydrophobic core of the amyloid β molecule interacts with the hydrophobic part of 24(S)hydroxycholesterol, but no hydrogen bonds with high stability were found. Using this procedure, globular amyloid β could retain 24(S)hydroxycholesterol and thus contribute to its pathological accumulation in the brains of patients with Alzheimer disease.
authors.affiliation: Alzheimer Disease Centre, Prague Psychiatric Centre, Ústavní 91, 181 03, Prague 8, Bohnice, Czech Republic. kristofikova@pcp.lf3.cuni.cz
authors.forename: Zdena
authors.initials: Z
authors.lastname: Krištofiková
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Kříž
authors.forename: Daniela
authors.initials: D
authors.lastname: Rípová
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Koča
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006624:Hippocampus / Q000378:metabolism; D006888:Hydroxycholesterols / Q000378:metabolism*; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016229:Amyloid beta-Peptides; D006888:Hydroxycholesterols; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C044563:24-hydroxycholesterol
references.citation: J Lipid Res. 2000 May;41(5):840-5
references.pmid: 10787445
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Biochemistry. 2005 Jan 11;44(1):157-64
references.pmid: 15628856
references.citation: J Biol Chem. 1997 May 9;272(19):12601-5
references.pmid: 9139713
references.citation: Mol Psychiatry. 2002;7(8):899-902
references.pmid: 12232784
references.citation: Chembiochem. 2006 Feb;7(2):257-67
references.pmid: 16444756
references.citation: Biopolymers. 1999 May;49(6):505-14
references.pmid: 10193196
references.citation: J Neurochem. 1998 May;70(5):2179-87
references.pmid: 9572306
references.citation: Nature. 1997 Oct 16;389(6652):689-95
references.pmid: 9338779
references.citation: Biophys J. 1995 Aug;69(2):640-51
references.pmid: 8527678
references.citation: J Mol Biol. 2004 Nov 26;344(3):757-67
references.pmid: 15533443
references.citation: J Physiol. 2006 Aug 15;575(Pt 1):5-10
references.pmid: 16809372
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10417-22
references.pmid: 12925731
references.citation: J Biol Chem. 1997 Mar 14;272(11):7431-6
references.pmid: 9054444
references.citation: Ann N Y Acad Sci. 1997 Apr 24;814:1-16
references.pmid: 9160955
references.citation: RNA. 2009 Jun;15(6):1219-30
references.pmid: 19369428
references.citation: Eur Psychiatry. 2009 Apr;24(3):183-90
references.pmid: 19286353
references.citation: Proteins. 2004 May 1;55(2):383-94
references.pmid: 15048829
references.citation: Neurosci Lett. 1997 Sep 26;234(1):71-3
references.pmid: 9347949
references.citation: J Neurochem. 2002 Dec;83(5):1110-9
references.pmid: 12437582
references.citation: Trends Neurosci. 2004 Jan;27(1):1-3
references.pmid: 14698599
references.citation: J Biol Chem. 1996 Jul 26;271(30):18032-44
references.pmid: 8663372
references.citation: J Mol Neurosci. 2008;34(1):35-43
references.pmid: 18157656
references.citation: Trends Neurosci. 1998 Jan;21(1):43-9
references.pmid: 9464686
references.citation: Acta Neurobiol Exp (Wars). 2004;64(1):71-9
references.pmid: 15190681
references.citation: Neurochem Res. 2008 Mar;33(3):412-21
references.pmid: 17717740
references.citation: Biochemistry. 2001 Jul 24;40(29):8563-71
references.pmid: 11456496
references.citation: Neurobiol Aging. 2011 Feb;32(2):235-48
references.pmid: 19324459
references.citation: J Pept Sci. 2004 May;10(5):229-48
references.pmid: 15160835
references.citation: Arch Gerontol Geriatr. 1993 Nov-Dec;17(3):179-88
references.pmid: 15374317
references.citation: Biochem Biophys Res Commun. 2007 Jul 20;359(1):46-50
references.pmid: 17532301
references.citation: J Biol Chem. 2004 Aug 13;279(33):34674-81
references.pmid: 15148325
references.citation: Lipids. 2007 Feb;42(1):5-14
references.pmid: 17393206
references.citation: Eur J Neurosci. 2010 Mar;31(5):788-96
references.pmid: 20374280
references.citation: J Chem Theory Comput. 2007 Nov;3(6):2312-34
references.pmid: 26636222
references.citation: Neurochem Res. 2001 Mar;26(3):203-12
references.pmid: 11495543
references.citation: Biophys J. 2000 Aug;79(2):934-44
references.pmid: 10920024