Point mutations in Aβ result in the formation of distinct polymorphic aggregates in the presence of lipid bilayers.
A hallmark of Alzheimer's disease (AD) is the rearrangement of the β-amyloid (Aβ) peptide to a non-native conformation that promotes the formation of toxic, nanoscale aggregates. Recent studies have pointed to the role of sample preparation in creating polymorphic fibrillar species. One of many potential pathways for Aβ toxicity may be modulation of lipid membrane function on cellular surfaces. There are several mutations clustered around the central hydrophobic core of Aβ near the α-secretase cleavage site (E22G Arctic mutation, E22K Italian mutation, D23N Iowa mutation, and A21G Flemish mutation). These point mutations are associated with hereditary diseases ranging from almost pure cerebral amyloid angiopathy (CAA) to typical Alzheimer's disease pathology with plaques and tangles. We investigated how these point mutations alter Aβ aggregation in the presence of supported lipid membranes comprised of total brain lipid extract. Brain lipid extract bilayers were used as a physiologically relevant model of a neuronal cell surface. Intact lipid bilayers were exposed to predominantly monomeric preparations of Wild Type or different mutant forms of Aβ, and atomic force microscopy was used to monitor aggregate formation and morphology as well as bilayer integrity over a 12 hour period. The goal of this study was to determine how point mutations in Aβ, which alter peptide charge and hydrophobic character, influence interactions between Aβ and the lipid surface. While fibril morphology did not appear to be significantly altered when mutants were prepped similarly and incubated under free solution conditions, aggregation in the lipid membranes resulted in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also had a variable ability to disrupt bilayer integrity.
The C Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia, United States of America.
Phillip M
PM
Pifer
Elizabeth A
EA
Yates
Justin
J
Legleiter
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism; D017354:Point Mutation; D055503:Protein Multimerization / Q000235:genetics
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008563:Membrane Lipids; D053829:Amyloid Precursor Protein Secretases
Acta Neurol Scand. 1989 Oct;80(4):319-23
2816288
Biochemistry. 2006 Sep 26;45(38):11532-9
16981713
J Mol Biol. 2004 Jan 16;335(3):833-42
14687578
J Biol Chem. 2003 Mar 28;278(13):11612-22
12499373
Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
17245412
Biophys J. 2000 Dec;79(6):3153-63
11106620
Biophys J. 2003 Oct;85(4):2430-41
14507706
J Neurosci. 2001 Sep 15;21(18):7226-35
11549733
Neurobiol Dis. 1998 Oct;5(4):281-6
9848098
Arch Biochem Biophys. 1979 Aug;196(1):165-77
507801
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7021-6
12773627
J Mol Biol. 2009 Mar 27;387(2):407-15
19133272
Nat Neurosci. 2001 Sep;4(9):887-93
11528419
Biochim Biophys Acta. 2004 Dec 24;1739(1):5-25
15607113
J Mol Biol. 2004 Jan 23;335(4):997-1006
14698294
J Biol Chem. 2001 Aug 31;276(35):32860-6
11441013
J Biol Chem. 2002 Aug 30;277(35):32046-53
12058030
FEBS Lett. 2004 Nov 5;577(1-2):117-20
15527771
Science. 2006 Nov 3;314(5800):781-4
17082448
Neurobiol Aging. 2008 Sep;29(9):1334-47
17403556
J Mol Biol. 2004 Jan 23;335(4):1039-49
14698298
Biochemistry. 2004 Jun 8;43(22):6959-67
15170333
Neurosci Lett. 2002 Jun 21;326(1):51-5
12052536
J Struct Biol. 2000 Jun;130(2-3):217-31
10940227
J Mol Biol. 1982 May 5;157(1):105-32
7108955
Biochem Biophys Res Commun. 2002 May 31;294(1):5-10
12054732
J Neuropathol Exp Neurol. 1997 Jul;56(7):751-61
9210871
J Neurochem. 1996 Feb;66(2):740-7
8592147
J Mol Biol. 2010 Aug 20;401(3):503-17
20600131
J Mol Biol. 2009 Feb 27;386(3):869-77
19038266
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3688-93
10097098
J Mol Biol. 2001 Aug 24;311(4):723-34
11518526
Protein Eng. 2002 Jun;15(6):513-20
12082170
Biophys J. 2007 Sep 15;93(6):1938-49
17526580
Nature. 2006 Mar 16;440(7082):352-7
16541076
J Mol Biol. 2000 Dec 15;304(5):953-65
11124039
J Colloid Interface Sci. 2004 Oct 1;278(1):96-106
15313642
Science. 1997 Jan 31;275(5300):651-3
9005848
J Biol Chem. 2002 Oct 25;277(43):40810-5
12181315
J Mol Biol. 2002 Apr 19;318(1):97-107
12054771
Neurosci Lett. 1993 Oct 14;161(1):17-20
7902973
Biophys J. 2001 Mar;80(3):1359-71
11222297
J Biol Chem. 2007 Aug 17;282(33):23818-28
17548355
Biochemistry. 2004 Aug 17;43(32):10302-7
15301528
Biochem J. 1999 Jun 15;340 ( Pt 3):703-9
10359654
Biochim Biophys Acta. 2004 Nov 3;1666(1-2):205-26
15519316
Eur J Neurosci. 2001 Jun;13(11):2015-24
11422442
Curr Opin Struct Biol. 2007 Feb;17(1):48-57
17251001
Brain Res Brain Res Rev. 1995 Sep;21(2):195-218
8866675
J Mol Biol. 2003 Sep 26;332(4):795-808
12972252
J Biol Chem. 1997 Aug 29;272(35):22364-72
9268388
J Biol Chem. 2002 Dec 27;277(52):50914-22
12356747
Biochem J. 2001 May 1;355(Pt 3):869-77
11311152
Biophys J. 2008 Nov 15;95(10):4845-61
18515395
Proc Natl Acad Sci U S A. 2009 May 5;106(18):7443-8
19376973
J Biol Chem. 2000 Sep 1;275(35):27110-6
10821838
Trends Neurosci. 1995 May;18(5):203-6
7610488
J Biol Chem. 2003 Nov 14;278(46):46179-87
12944403
J Neurosci. 2004 Nov 10;24(45):10191-200
15537891
Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10427-32
16020533
J Mol Biol. 2008 Jan 18;375(3):695-707
18036611
Biochem J. 2000 Jul 1;349(Pt 1):299-308
10861242
Curr Opin Struct Biol. 2003 Apr;13(2):146-59
12727507
Science. 2005 Jan 14;307(5707):262-5
15653506