title: Embedding Aβ42 in heterogeneous membranes depends on cholesterol asymmetries.
abstract: Using a coarse-grained lipid and peptide model, we show that the free energy stabilization of amyloid-β in heterogeneous lipid membranes is predicted to have a dependence on asymmetric distributions of cholesterol compositions across the membrane leaflets. We find that a highly asymmetric cholesterol distribution that is depleted on the exofacial leaflet but enhanced on the cytofacial leaflet of the model lipid membrane thermodynamically favors membrane retention of a fully embedded Aβ peptide. However, in the case of cholesterol redistribution that increases concentration of cholesterol on the exofacial layer, typical of aging or Alzheimer's disease, the free energy favors peptide extrusion of the highly reactive N-terminus into the extracellular space that may be vulnerable to aggregation, oligomerization, or deleterious oxidative reactivity.
authors: Department of Physics, University of Roma Tre, Roma, Italy.
authors: Nicoletta
authors: N
authors: Liguori
authors: Paul S
authors: PS
authors: Nerenberg
authors: Teresa
authors: T
authors: Head-Gordon
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry*; D004058:Diffusion; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D010446:Peptide Fragments / Q000378:metabolism*; D011487:Protein Conformation; D013569:Synapses / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002784:Cholesterol
references: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3348-53
references: 19204293
references: Neurobiol Aging. 1984 Winter;5(4):323-33
references: 6397694
references: Biochemistry. 1969 Nov;8(11):4606-12
references: 4311035
references: Chembiochem. 2006 Feb;7(2):257-67
references: 16444756
references: Neuroreport. 2002 Mar 25;13(4):383-6
references: 11930145
references: J Biol Chem. 2002 Feb 22;277(8):6273-9
references: 11741923
references: Biopolymers. 1983 Dec;22(12):2577-637
references: 6667333
references: Science. 2006 Nov 3;314(5800):777-81
references: 17082447
references: Nat Rev Neurosci. 2011 May;12(5):284-96
references: 21448224
references: J Phys Chem B. 2010 Feb 4;114(4):1652-60
references: 20055378
references: Biochim Biophys Acta. 2003 Nov 15;1634(3):61
references: 14643793
references: Phys Rev A Gen Phys. 1985 Mar;31(3):1695-1697
references: 9895674
references: J Lipid Res. 2008 Jun;49(6):1157-75
references: 18334715
references: Neurobiol Aging. 2002 Sep-Oct;23(5):685-94
references: 12392774
references: Biophys J. 2004 Apr;86(4):2231-7
references: 15041662
references: BMC Struct Biol. 2006 Oct 19;6:21
references: 17052343
references: J Comput Chem. 2009 Oct;30(13):2157-64
references: 19229944
references: J Biol Chem. 1999 Jun 25;274(26):18801-7
references: 10373497
references: Biochim Biophys Acta. 2010 Aug;1801(8):774-83
references: 20117236
references: Biochim Biophys Acta. 2007 Aug;1768(8):1952-65
references: 17490607
references: Protein Sci. 2011 Sep;20(9):1530-45
references: 21692120
references: J Mol Biol. 2008 Feb 15;376(2):393-404
references: 18164313
references: J Neurochem. 1996 Apr;66(4):1717-25
references: 8627330
references: J Neurochem. 2011 Mar;116(5):684-9
references: 21214553
references: J Neurochem. 1991 Jun;56(6):2051-9
references: 2027013
references: J Mol Biol. 2000 Feb 25;296(3):911-9
references: 10677291
references: Biochim Biophys Acta. 2010 Oct;1798(10):1969-76
references: 20603101
references: Neurosci Biobehav Rev. 2009 Jul;33(7):1099-108
references: 19481107
references: Biophys J. 2005 Jun;88(6):4434-8
references: 15805166
references: J Chem Theory Comput. 2008 Jan;4(1):116-22
references: 26619985
references: Biochim Biophys Acta. 2010 Aug;1801(8):750-3
references: 20471492
references: Biochim Biophys Acta. 2008 Dec;1778(12):2710-6
references: 18706389
references: Eur J Biochem. 2002 Nov;269(22):5642-8
references: 12423364
references: J Am Chem Soc. 2009 Oct 28;131(42):15194-202
references: 19795891
references: Biochemistry. 2008 Sep 9;47(36):9428-46
references: 18702528
references: Eur Biophys J. 2006 Aug;35(6):523-31
references: 16670880
references: Acta Neuropathol. 1997 Oct;94(4):345-52
references: 9341935
references: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5644-51
references: 16567625
references: Neurobiol Aging. 1992 May-Jun;13(3):413-9
references: 1625771
references: J Chem Phys. 2007 Jan 7;126(1):014101
references: 17212484
references: Biochem Biophys Res Commun. 1996 May 6;222(1):78-82
references: 8630078
references: J Neurochem. 1994 Nov;63(5):1802-11
references: 7931336
references: J Mol Biol. 2012 Aug 24;421(4-5):561-71
references: 22108168
references: Chem Soc Rev. 2013 Aug 21;42(16):6801-22
references: 23708257