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Cholesterol inhibits the insertion of the Alzheimer’s peptide Aβ(25–35) in lipid bilayers

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Abstract

The physiological relationship between brain cholesterol content and the action of amyloid β (Aβ) peptide in Alzheimer’s disease (AD) is a highly controversially discussed topic. Evidences for modulations of the Aβ/membrane interaction induced by plasma membrane cholesterol have already been observed. We have recently reported that Aβ(25–35) is capable of inserting in lipid membranes and perturbing their structure. Applying neutron diffraction and selective deuteration, we now demonstrate that cholesterol alters, at the molecular level, the capability of Aβ(25–35) to penetrate into the lipid bilayers; in particular, a molar weight content of 20% of cholesterol hinders the intercalation of monomeric Aβ(25–35) completely. At very low cholesterol content (about 1% molar weight) the location of the C-terminal part of Aβ(25–35) has been unequivocally established in the hydrocarbon region of the membrane, in agreement with our previous results on pure phospholipids membrane. These results link a structural property to a physiological and functional behavior and point to a therapeutical approach to prevent the AD by modulation of membrane properties.

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References

  • Albert AD, Young JE, Yeagle PL (1996) Rhodopsin–cholesterol interactions in bovine rod outer segment disk membranes. Biochim Biophys Acta 1285:47–55

    Article  Google Scholar 

  • Arispe N, Doh M (2002) Plasma membrane cholesterol controls the cytotoxicity of Alzheimer’s disease AβP (1–40) and (1–42) peptides. FASEB J 16:1526–1536

    Article  Google Scholar 

  • Arispe N, Pollard HB, Rojas E (1996) Zn2+ interaction with Alzheimer amyloid β protein calcium channels. Proc Natl Acad Sci USA 93:1710–1715

    Article  ADS  Google Scholar 

  • Busciglio J, Hartmann H, Lorenzo A, Wong C, Baumann K, Sommer B, Staufenbiel M, Yankner BA (1997) Neuronal localization of presenilin-1 and association with amyloid plaques and neurofibrillary tangles in Alzheimer’s disease. J Neurosci 17:5101–5107

    Google Scholar 

  • Cornelius F (1995) Cholesterol modulation of molecular activity of reconstituted shark Na+,K(+)-ATPase. Biochim Biophys Acta 1235:205–212

    Article  Google Scholar 

  • Curtain CC, Ali FE, Smith DG, Bush AI, Masters CL, Barnham KJ (2003) Metal ions, pH, and cholesterol regulate the interactions of Alzheimer’s disease amyloid-β peptide with membrane lipid. J Biol Chem 278:2977–2982

    Article  Google Scholar 

  • Dante S, Hauß T, Dencher NA (2002) β-amyloid 25 to 35 is intercalated in anionic and zwitterionic lipid membranes to different extents. Biophys J 83:2610–2616

    Google Scholar 

  • Dante S, Hauß T, Dencher NA (2003) Insertion of externally administered amyloid β peptide 25–35 and perturbation of lipid bilayers. Biochemistry 42:13667–13672

    Article  Google Scholar 

  • Eckert GP, Cairns NJ, Maras A, Gattaz WF, Müller WE (2000) Cholesterol modulates the membrane-disordering effects of β-amyloid peptides in the hippocampus: specific changes in Alzheimer’s disease. Dement Geriatr Cogn Disord 11:181–186

    Article  Google Scholar 

  • Eckert GP, Kirsch C, Leutz S, Wood WG, Müller WE (2003) Cholesterol modulates amyloid β-peptide’s membrane interactions. Pharmacopsychiatry 36(Suppl 2):S136–S143

    Google Scholar 

  • Fassbender K, Masters C, Beyreuther K (2001) Alzheimer’s disease: molecular concepts and therapeutic targets. Naturwissenschaften 88:261–267

    Article  ADS  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  ADS  Google Scholar 

  • Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM, Teplow DB, Selkoe DJ (1999) Protofibrillar intermediates of amyloid β-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19:8876–8884

    Google Scholar 

  • Hartmann T (2001) Cholesterol, A beta and Alzheimer’s disease. Trends Neurosci 24:S45–S48

    Article  Google Scholar 

  • Heller H, Schaefer M, Schulten K (1993) Molecular dynamics simulation of a bilayer of 200 lipids in the gel and in the liquid-crystal phase. J Phys Chem 97:8343–8360

    Article  Google Scholar 

  • Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci USA 96:3228–3233

    Article  ADS  Google Scholar 

  • Jao SC, Ma K, Talafous J, Orlando R, Zagorski MG (1997) Trifluoroacetic acid pretreatment reproducibly disaggregates the amyloid β-peptide. Amyloid Int J Exp Clin Invest 4:240–244

    Google Scholar 

  • Ji SR, Wu Y, Sui SF (2002a) Cholesterol is an important factor affecting the membrane insertion of β-amyloid peptide (Aβ 1–40), which may potentially inhibit the fibril formation. J Biol Chem 277:6273–6279

    Article  Google Scholar 

  • Ji SR, Wu Y, Sui SF (2002b) Study of beta-amyloid peptide (Abeta40) insertion into phospholipid membranes using monolayer technique. Biochemistry (Mosc) 67:1283–1288

    Article  Google Scholar 

  • Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA (2000) Statins and the risk of dementia. Lancet 356:1627–1631

    Article  Google Scholar 

  • Kawahara M, Kuroda Y (2000) Molecular mechanism of neurodegeneration induced by Alzheimer’s β-amyloid protein: channel formation and disruption of calcium homeostasis. Brain Res Bull 53:389–397

    Article  Google Scholar 

  • Kawahara M, Kuroda Y (2001) Intracellular calcium changes in neuronal cells induced by Alzheimer’s beta-amyloid protein are blocked by estradiol and cholesterol. Cell Mol Neurobiol 21:1–13

    Article  Google Scholar 

  • Kohno T, Kobayashi K, Maeda T, Sato K, Takashima A (1996) Three-dimensional structures of the amyloid β peptide (25–35) in membrane-mimicking environment. Biochemistry 35:16094–16104

    Article  Google Scholar 

  • Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F (2001) Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10. Proc Natl Acad Sci USA 98:5815–5820

    Article  ADS  Google Scholar 

  • Koudinov AR, Koudinova NV (2001) Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J 15:1858–1860

    Google Scholar 

  • Koudinov AR, Koudinova NV (2003) Cholesterol, synaptic function and Alzheimer’s disease. Pharmacopsychiatry 36(Suppl 2):S107–S112

    Google Scholar 

  • Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453

    Article  ADS  Google Scholar 

  • Lasalde JA, Colom A, Resto E, Zuazaga C (1995) Heterogeneous distribution of acetylcholine receptors in chick myocytes induced by cholesterol enrichment. Biochim Biophys Acta 1235:361–368

    Article  Google Scholar 

  • Lin MC, Kagan BL (2002) Electrophysiologic properties of channels induced by Aβ(25–35) in planar lipid bilayers. Peptides 23:1215–1228

    Article  Google Scholar 

  • Mason RP, Shoemaker WJ, Shajenko L, Chambers TE, Herbette LG (1992) Evidence for changes in the Alzheimer’s disease brain cortical membrane structure mediated by cholesterol. Neurobiol Aging 13:413–419

    Article  Google Scholar 

  • McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL (1999) Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46:860–866

    Article  Google Scholar 

  • Micelli S, Meleleo D, Picciarelli V, Gallucci E (2004) Effects of sterols on β-amyloid peptide (AβP 1–40) channel formation and their properties in planar lipid membranes. Biophys J 86:2231–2237

    Article  Google Scholar 

  • Mirzabekov T, Lin MC, Yuan WL, Marshall PJ, Carman M, Tomaselli K, Lieberburg I, Kagan BL (1994) Channel formation in planar lipid bilayers by a neurotoxic fragment of the β-amyloid peptide. Biochem Biophys Res Commun 202:1142–1148

    Article  Google Scholar 

  • Müller WE, Hartmann H, Eckert GP, Eckert A, Eisert S (1997) Cholesterol affects neuronal calcium signalling. A possible link between apolipoprotein polymorphism, β-amyloid neurotoxicity, and neurodegeneration in Alzheimer’s disease. Nutr Metab Cardiovasc Dis 7:210–216

    Google Scholar 

  • Papadopoulos G, Hauß T (2003) Determination of the number of water molecules in the proton pathway of bacteriorhodopsin using neutron diffraction data. Eur Biophys J 32:392–401

    Article  Google Scholar 

  • Rappolt M, Vidal MF, Kriechbaum M, Steinhart M, Amenitsch H, Bernstorff S, Laggner P (2003) Structural, dynamic and mechanical properties of POPC at low cholesterol concentration studied in pressure/temperature space. Eur Biophys J 31:575–585

    Google Scholar 

  • Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA (2000) Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis 7:321–331

    Article  Google Scholar 

  • Scarpini E, Scheltens P, Feldman H (2003) Treatment of Alzheimer’s disease: current status and new perspectives. Lancet Neurol 2:539–547

    Article  Google Scholar 

  • Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:A23–A31

    Article  ADS  Google Scholar 

  • Sparks DL, Hunsaker JC, Scheff SW, Kryscio RJ, Henson JL, Markesbery WR (1990) Cortical senile plaques in coronary artery disease, aging and Alzheimer’s disease. Neurobiol Aging 11:601–607

    Article  Google Scholar 

  • Whetton AD, Gordon LM, Houslay MD (1983) Elevated membrane cholesterol concentrations inhibit glucagon-stimulated adenylate cyclase. Biochem J 210:437–449

    Google Scholar 

  • Wolozin B (2001) A fluid connection: cholesterol and Aβ. Proc Natl Acad Sci USA 98:5371–5373

    Article  ADS  Google Scholar 

  • Wolozin B (2002) Cholesterol and Alzheimer’s disease. Biochem Soc Trans 30:525–529

    Article  Google Scholar 

  • Wood WG, Schroeder F, Igbavboa U, Avdulov NA, Chochina SV (2002) Brain membrane cholesterol domains, aging and amyloid β-peptides. Neurobiol Aging 23:685–694

    Article  Google Scholar 

  • Yip CM, Elton EA, Darabie AA, Morrison MR, McLaurin J (2001) Cholesterol, a modulator of membrane-associated Aβ-fibrillogenesis and neurotoxicity. J Mol Biol 311:723–734

    Article  Google Scholar 

  • Zhou Y, Richardson JS (1996) Cholesterol protects PC12 cells from β-amyloid induced calcium disordering and cytotoxicity. Neuroreport 7:2487–2490

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by Grant 03-DEE8DA from Bundesministerium für Bildung und Forschung, by the Fonds der Chemischen Industrie and by the Research Center Jülich (F + E) (to N.A.D).

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Authors and Affiliations

  1. Physical Biochemistry, Darmstadt University of Technology, Petersenstrasse 22, 64287, Darmstadt, Germany

    Silvia Dante, Thomas Hauß & Norbert A. Dencher

  2. SF2-BENSC, Hahn-Meitner-Institut, Glienicker Strasse 100, 14109, Berlin, Germany

    Silvia Dante & Thomas Hauß

Authors
  1. Silvia Dante
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  2. Thomas Hauß
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  3. Norbert A. Dencher
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Correspondence to Silvia Dante.

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Dante, S., Hauß, T. & Dencher, N.A. Cholesterol inhibits the insertion of the Alzheimer’s peptide Aβ(25–35) in lipid bilayers. Eur Biophys J 35, 523–531 (2006). https://doi.org/10.1007/s00249-006-0062-x

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