Cholesterol Modulates Amyloid Beta-peptide’s Membrane Interactions (original) (raw)

Pharmacopsychiatry 2003; 36: 136-143
DOI: 10.1055/s-2003-43059

Original Paper

© Georg Thieme Verlag Stuttgart · New York

Gunter P. Eckert1 , Christopher Kirsch1 , Steffen Leutz1 , W. Gibson Wood2 , Walter E. Müller1

• 1Department of Pharmacology, Biocenter Niederursel, University of Frankfurt, Germany
• 2Geriatric Research, Education and Clinical Center, VA Medical Center (11G), Department of Pharmacology, University of Minnesota School of Medicine, Minneapolis, MN, USA

Further Information

Publication History

Publication Date:
22 October 2003 (online)

Abstract

The causal relationship between amyloid beta-peptide (Aβ) deposition and Alzheimer’s disease (AD)-specific neuropathological lesions such as neurodegeneration and cortical atrophy is still not known. Mounting evidence points to alterations in cholesterol homeostasis occurring in AD brain that are probably linked to cerebral Aβ pathology. Interestingly, cholesterol not only modulates Aβ synthesis, but also controls interactions between Aβ and neuronal membranes that are regarded as decisive in the initiation of a neurotoxic cascade. This review focuses on the impact of cholesterol on membrane disordering effects of Aβ. Cholesterol is known to be an essential modulator of physicochemical state and functional activity in physiological membranes, and thus plays an essential role in the regulation of synaptic function and cell plasticity. In vitro and in vivo modulation of membrane cholesterol levels affect different cholesterol pools within the plasma membrane bilayer that are differentially sensitive to Aβ’s disrupting effects. Membrane acyl-chains in the hydrocarbon core are most susceptible to Aβ. In this membrane region, cholesterol attenuates the membrane disordering effects of Aβ. This cholesterol pool is modulated by methyl-beta-cyclodextrin (MβCD) treatment in vitro. On the other hand, statin treatment in vivo depletes a cholesterol pool in a membrane area, which is much less susceptible to Aβ’s membrane-disrupting effects. Our findings clearly implicate an involvement of cholesterol in brain membrane alterations occurring during AD. Disease-related changes in membrane cholesterol metabolism may be subtle and restricted to defined membrane pools since total membrane cholesterol levels are mainly unchanged in AD brain. Thus, elucidation of the structure and function of different cholesterol pools is necessary in understanding the coherence between cholesterol and AD.

Abbreviations

Aβ:amyloid beta-peptide

ADAlzheimer’s disease;

ApoEapolipoprotein E

APPamyloid beta-peptide precursor protein

BBBblood brain barrier

CHOD-PAP-cholesteroloxidase-peroxidase-aminophenazonmethodphenol method

CNScentral nervous system

DPHdiphenylhexatriene

HMG-CoAhydroxymethylglutaryl-coenzyme A

MβCDmethyl-beta-cyclodextrin

PMplasma membrane

SPMsynaptosomal plasma membrane

SUVsmall unilammelar vesicle

TNBStrinitrobenzensulfonic acid

TMA-DPHtrimethylammonium-diphenylhexatriene

Key words

Cholesterol - Statins - Brain membrane - Alzheimer’s Disease - Amyloid

References

• 1 Abe K, Saito H. Cholesterol does not affect the toxicity of amyloid beta fragment but mimics its effect on MTT formazan exocytosis in cultured rat hippocampal neurons. Neurosci Res. 1999; 35 165-174
• 2 Arispe N, Doh M. Plasma membrane cholesterol controls the cytotoxicity of Alzheimer's disease Aβ (1 - 40) and (1 - 42) peptides. FASEB J. 2002; 16 1526-1536
• 3 Bastiaanse E ML, Hoeld K M, Van der Laarse A. The effect of membrane cholesterol content on ion transport processes in plasma membranes. Cardiovasc Res. 1997; 33 272-283
• 4 Bodovitz S, Klein W L. Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem. 1996; 271 4436-4440
• 5 Brown D A, London E. Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol. 1998; 14 111-136
• 6 Eckert G P, Cairns N J, Maras A, Gattaz W F, Müller W E. Cholesterol modulates the membrane-disordering effects of beta-amyloid peptides in the hippocampus: specific changes in Alzheimer's disease. Dement Geriatr Cogn Disord. 2000; 11 181-186
• 7 Eckert G P, Igbavboa U, Müller W E, Wood W G. Lipid rafts of purified mouse brain synaptosomes prepared with or without detergent reveal different lipid and protein domains. Brain Res. 2003; 962 144-150
• 8 Eckert G P, Kirsch C, Mueller W E. Differential effects of lovastatin treatment on brain cholesterol levels in normal and apoE-deficient mice. Neuroreport. 2001; 12 883-887
• 9 Eckert G P, Kirsch C, Müller W E. Brain-Membrane Cholesterol in Alzheimer's Disease. J Nutr Health Aging. 2003; 7 18-23
• 10 Eckert G P, Wood W G, Müller W E. Effects of aging and beta-amyloid on the properties of brain synaptic and mitochondrial membranes. J Neural Transm. 2001; 108 1051-1064
• 11 Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T. Simvastatin strongly reduces levels of Alzheimer's disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U.S.A. 2001; 98 5856-5861
• 12 Gimpl G, Burger K, Fahrenholz F. Cholesterol as modulator of receptor function. Biochemistry. 1997; 36 10 959-10 974
• 13 Hartmann H, Eckert A, Müller W E. Apolipoprotein E and cholesterol affect neuronal calcium signalling: The possible relationship to beta-amyloid neurotoxicity. Biochem Biophys Res Commun. 1994; 200 1185-1192
• 14 Howland D S, Trusko S P, Savage M J, Reaume A G, Lang D M, Hirsch J D, Maeda N, Siman R, Greenberg B D, Scott R W, Flood D G. Modulation of secreted beta-amyloid precursor protein and amyloid beta-peptide in brain by cholesterol. J Biol Chem. 1998; 273 16 576-16 582
• 15 Igbavboa U, Avdulov N A, Chochina S V, Wood W G. Transbilayer distribution of cholesterol is modified in brain synaptic plasma membranes of knockout mice deficient in the low-density lipoprotein receptor, apolipoprotein E, or both proteins. J Neurochem. 1997; 69 1661-1667
• 16 Igbavboa U, Avdulov N A, Schroeder F, Wood W G. Increasing age alters transbilayer fluidity and cholesterol asymmetry in synaptic plasma membrane of mice. J Neurochem. 1996; 66 1717-1725
• 17 Ikonen E. Roles of lipid rafts in membrane transport. Curr Opin Cell Biol. 2001; 13 470-477
• 18 Jick H, Zornberg G L, Jick S S, Seshadri S, Drachman D A. Statins and the risk of dementia. Lancet. 2000; 356 1627-1631
• 19 Kaiser R D, London E. Location of diphenylhexatriene (DPH) and its derivatives within membranes: comparison of different fluorescence quenching analyses of membrane depth. Biochemistry. 1998; 37 8180-8190
• 20 Kanfer J N, Sorrentino G, Sitar D S. Amyloid beta peptide membrane perturbation is the basis for its biological effects. Neurochem Res. 1999; 24 1621-1630
• 21 Kawahara M, Kuroda Y. Molecular mechanism of neurodegeneration induced by Alzheimer's beta-amyloid protein: channel formation and disruption of calcium homeostasis. Brain Res Bull. 2000; 53 389-397
• 22 Kirsch C, Eckert G P, Koudinov A, Müller W E. Brain Cholesterol, Statins and Alzheimer's Disease. Pharmacopsychiatry (Suppl) 2003; in press
• 23 Kirsch C, Eckert G P, Müller W E. Cholesterol attenuates the membrane perturbing properties of β-amyloid peptides. Amyloid. 2002; 9 149-159
• 24 Kirsch C, Eckert G P, Müller W E. Statins affect cholesterol micro-domains in brain plasma membranes. Biochem Pharmacol. 2003; 65 843-856
• 25 Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc Natl Acad Sci USA. 2001; 98 5815-5820
• 26 Koudinov A R, Koudinova N V. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 2001; 15 1858-1860
• 27 Liscum L, Munn N J. Intracellular cholesterol transport. Biochim Biophys Acta. 1999; 1438 19-37
• 28 Mason R P, Shoemaker W J, Shajenko L, Chambers T E, Herbette L G. Evidence for changes in the Alzheimer's disease brain cortical membrane structure mediated by cholesterol. Neurobiol Aging. 1992; 13 413-419
• 29 Mason R P, Shoemaker W J, Shajenko L, Herbette L G. X-ray diffraction analysis of brain lipid membrane structure in Alzheimer's disease and beta-amyloid peptide interactions. Ann N Y Acad Sci. 1993; 695 54-58
• 30 Mecocci P, Cherubini A, Beal M F, Cecchetti R, Chionne F, Polidori M C, Romano G, Senin U. Altered mitochondrial membrane fluidity in AD brain. Neurosci Lett. 1996; 207 129-132
• 31 Müller WE; Eckert GP; Scheuer K; Cairns NJ; Maras A; Gattaz W F. Effects of beta-amyloid peptides on the fluidity of membranes from frontal and parietal lobes of human brain. High potencies of A beta 1 - 42 and A beta 1 - 43. Amyloid. 1998; 5 10-15
• 32 Müller W E, Kirsch C, Eckert G P. Membrane-disordering effects of beta-amyloid peptides. Biochem Soc Trans. 2001; 29 617-623
• 33 Müller W E, Koch S, Eckert A, Hartmann H, Scheuer K. Beta-Amyloid peptide decreases membrane fluidity. Brain Res. 1995; 674 133-136
• 34 Puglielli L, Konopka G, Pack-Chung E, Ingano L A, Berezovska O, Hyman B T, Chang T Y, Tanzi R E, Kovacs D M. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol. 2001; 3 905-912
• 35 Ramjiawan B, Czubryt M P, Gilchrist J SC, Pierce G N. Nuclear membrane cholesterol can modulate nuclear nucleoside triphosphatase activity. J Cell Biochem. 1996; 63 442-452
• 36 Scheuer K, Maras A, Gattaz W F, Cairns N, Förstl H, Müller W E. Cortical NMDA Receptor Properties and Membrane Fluidity are Altered in Alzheimer’s Disease. Dementia. 1996; 7 210-214
• 37 Schroeder F, Frolov A A, Murphy E J, Atshaves B P, Jefferson J R, Pu L X, Wood W G, Foxworth W B, Kier A B. Recent advances in membrane cholesterol domain dynamics and intracellular cholesterol trafficking. Proc Soc Exp Biol Med. 1996; 213 150-177
• 38 Simons K, Ikonen E. How cells handle cholesterol. Science. 2000; 290 1721-1726
• 39 Simons K, Toomre D. Lipid Rafts and Signal Transduction. Nat Rev Mol Cell Biol. 2000; 1 31-39
• 40 Simons M, Keller P, De Strooper B, Beyreuther K, Dotti C G, Simons K. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA. 1998; 95 6460-6464
• 41 Singer S J, Nicolson G L. The fluid mosaic model of the structure of cell membranes. Science. 1972; 175 720-731
• 42 Svennerholm L, Gottfries C G. Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late-onset form (type II). J Neurochem. 1994; 62 1039-1047
• 43 Thiele C, Hannah M J, Fahrenholz F, Huttner W B. Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nat Cell Biol. 2000; 2 42-49
• 44 Waschuk S, Elton E A, Darabie A A, Fraser P E, McLaurin J. Cellular membrane composition defines Aβ-lipid interactions. J Biol Chem. 2001; 276 33 561-33 568
• 45 Wolozin B. Cholesterol and Alzheimer's disease. Biochem Soc Trans. 2002; 30 525-529
• 46 Wolozin B, Kellman W, Ruosseau P, Celesia G G, Siegel G. Decreased prevalence of alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000; 57 1439-1443
• 47 Wood W G, Eckert G P, Igbavboa U, Müller W E. Amyloid beta-protein interactions with membranes and cholesterol: causes and casualties of Alzheimer’s disease. Biochim Biophys Acta. 2003; 1610 281-290
• 48 Wood W G, Schroeder F, Avdulov N A, Chochina S V, Igbavboa U. Recent advances in brain cholesterol dynamics: transport, domains, and Alzheimer's disease. Lipids. 1999; 34 225-234
• 49 Wood W G, Schroeder F, Igbavboa U, Avdulov N A, Chochina S V. Brain membrane cholesterol domains, aging and amyloid beta-peptides. Neurobiol Aging. 2002; 23 685
• 50 Yamaguchi H, Maat-Schieman M L, van Duinen S G, Prins F A, Neeskens P, Natte R, Roos R A. Amyloid beta protein (Abeta) starts to deposit as plasma membrane-bound form in diffuse plaques of brains from hereditary cerebral hemorrhage with amyloidosis-Dutch type, Alzheimer disease and nondemented aged subjects. J Neuropathol Exp Neurol. 2000; 59 723-732
• 51 Yankner B A, Duffy L K, Kirschner D A. Neurotrophic and neurotoxic effects of amyloid - beta protein: Reversal by tachykinin neuropeptides. Science. 1990; 250 279-282
• 52 Yip C M, Darabie A A, McLaurin J. Abeta 1 - 42-Peptide assembly on lipid bilayers. J Mol Biol. 2002; 318 97-107
• 53 Zhou Y, Richardson J S. Cholesterol protects PC12 cells from beta-amyloid induced calcium disordering and cytotoxicity. Neuroreport. 1996; 7 2487-2490

Dr. Gunter P. Eckert

Department of Pharmacology

Biocenter Niederursel

Phone: +49 (69) 79 82 93 78

Fax: +49 (69) 79 82 93 74

Email: G.P.Eckert@em.uni-frankfurt.de