title: The aqueous phase of Alzheimer's disease brain contains assemblies built from ∼4 and ∼7 kDa Aβ species.
abstract: BACKGROUND
  Much knowledge about amyloid β (Aβ) aggregation and toxicity has been acquired using synthetic peptides and mouse models, whereas less is known about soluble Aβ in human brain.
  
  
  METHODS
  We analyzed aqueous extracts from multiple AD brains using an array of techniques.
  
  
  RESULTS
  Brains can contain at least four different Aβ assembly forms including: (i) monomers, (ii) a ∼7 kDa Aβ species, and larger species (iii) from ∼30-150 kDa, and (iv) >160 kDa. High molecular weight species are by far the most prevalent and appear to be built from ∼7 kDa Aβ species. The ∼7 kDa Aβ species resist denaturation by chaotropic agents and have a higher Aβ42/Aβ40 ratio than monomers, and are unreactive with antibodies to Asp1 of Ab or APP residues N-terminal of Asp1.
  
  
  CONCLUSIONS
  Further analysis of brain-derived ∼7 kDa Aβ species, the mechanism by which they assemble and the structures they form should reveal therapeutic and diagnostic opportunities.
authors.affiliation: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Mc Donald
authors.affiliation: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Republic of Ireland.
authors.forename: Tiernan T
authors.initials: TT
authors.lastname: O'Malley
authors.affiliation: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Mably
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Göteborg, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Brinkmalm
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Göteborg, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.affiliation: Wyatt Technology Corporation, Woburn, MA, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Wittbold
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Massachusetts General Institute for Neurodegenerative Disease, Charlestown, MA, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA. Electronic address: dwalsh3@partners.org.
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D008970:Molecular Weight; D055503:Protein Multimerization; D013702:Temporal Lobe / Q000378:metabolism*; D014867:Water / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D014867:Water
keywords: Alzheimer's disease; Amyloid β-protein; Oligomers; SDS-Stable dimer
references.citation: Hybridoma. 1995 Jun;14(3):235-42
references.pmid: 7590785
references.citation: Ann Neurol. 1999 Dec;46(6):860-6
references.pmid: 10589538
references.citation: Amyloid. 2005 Jun;12(2):88-95
references.pmid: 16011984
references.citation: Am J Pathol. 1999 Jan;154(1):271-9
references.pmid: 9916941
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1550-5
references.pmid: 9037091
references.citation: Science. 2002 Jul 19;297(5580):353-6
references.pmid: 12130773
references.citation: Anal Chem. 1987 May 1;59(9):1332-9
references.pmid: 3605623
references.citation: J Exp Med. 2012 Nov 19;209(12):2149-56
references.pmid: 23129750
references.citation: Nat Neurosci. 2012 Mar;15(3):349-57
references.pmid: 22286176
references.citation: Biochemistry. 2006 Dec 26;45(51):15157-67
references.pmid: 17176037
references.citation: Neurobiol Aging. 2013 May;34(5):1315-27
references.pmid: 23182244
references.citation: Brain. 2013 May;136(Pt 5):1383-98
references.pmid: 23576130
references.citation: Nat Med. 2008 Aug;14(8):837-42
references.pmid: 18568035
references.citation: Biochem J. 2014 Aug 1;461(3):413-26
references.pmid: 24785004
references.citation: Biochemistry. 2014 Jun 24;53(24):3908-21
references.pmid: 24840308
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3502-6
references.pmid: 19204288
references.citation: Ann Neurol. 2013 Jan;73(1):104-19
references.pmid: 23225543
references.citation: J Neurosci. 2011 Oct 12;31(41):14488-95
references.pmid: 21994365
references.citation: Nat Neurosci. 2001 Sep;4(9):887-93
references.pmid: 11528419
references.citation: Exp Neurol. 1999 Aug;158(2):328-37
references.pmid: 10415140
references.citation: FEBS J. 2009 Mar;276(5):1266-81
references.pmid: 19175671
references.citation: Alzheimers Res Ther. 2015 Mar 22;7(1):14
references.pmid: 25802556
references.citation: J Neurosci. 2010 Oct 27;30(43):14411-9
references.pmid: 20980598
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5819-24
references.pmid: 21421841
references.citation: Prog Mol Biol Transl Sci. 2012;107:101-24
references.pmid: 22482449
references.citation: Nat Commun. 2011;2:336
references.pmid: 21654636
references.citation: Psychiatry Clin Neurosci. 2000 Feb;54(1):45-54
references.pmid: 15558879
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11848-53
references.pmid: 21712440
references.citation: Arch Neurol. 2009 Feb;66(2):190-9
references.pmid: 19204155
references.citation: J Biol Chem. 2005 Apr 29;280(17):17458-63
references.pmid: 15728175
references.citation: J Biol Chem. 1995 Jan 13;270(2):823-9
references.pmid: 7822317
references.citation: J Neurosci. 2012 Oct 24;32(43):15181-92
references.pmid: 23100439
references.citation: EMBO J. 2011 Jun 1;30(11):2255-65
references.pmid: 21527912
references.citation: J Biol Chem. 1995 Apr 21;270(16):9564-70
references.pmid: 7721886
references.citation: Biochem J. 2000 Oct 15;351 Pt 2:509-16
references.pmid: 11023838
references.citation: Curr Alzheimer Res. 2009 Aug;6(4):399-406
references.pmid: 19689240
references.citation: J Chromatogr. 1989 Jan 6;461:73-87
references.pmid: 2708482
references.citation: J Proteome Res. 2006 Apr;5(4):1010-6
references.pmid: 16602710
references.citation: Acta Neuropathol. 2013 Apr;125(4):549-64
references.pmid: 23354835
references.citation: J Biol Chem. 2009 Nov 20;284(47):32895-905
references.pmid: 19759000
references.citation: Electrophoresis. 1991 May;12(5):352-66
references.pmid: 1718736
references.citation: Trends Neurosci. 2001 Apr;24(4):219-24
references.pmid: 11250006
references.citation: J Neurochem. 2012 Jan;120 Suppl 1:149-66
references.pmid: 22121980
references.citation: FASEB J. 2013 Aug;27(8):3239-48
references.pmid: 23640054
references.citation: Nat Neurosci. 2012 Sep;15(9):1227-35
references.pmid: 22820466
references.citation: Brain Res. 2012 Apr 23;1450:138-47
references.pmid: 22440675
references.citation: Alzheimers Res Ther. 2012 May 23;4(3):18
references.pmid: 22621179
references.citation: Cold Spring Harb Perspect Med. 2012 Oct;2(10). pii: a006296. doi: 10.1101/cshperspect.a006296
references.pmid: 23028126
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):11025-30
references.pmid: 22711819
references.citation: Nature. 1992 Sep 24;359(6393):325-7
references.pmid: 1406936
references.citation: J Biol Chem. 1996 Sep 13;271(37):22908-14
references.pmid: 8798471
references.citation: Brain. 2010 May;133(Pt 5):1328-41
references.pmid: 20403962
references.citation: Neurosci Lett. 2014 Jun 24;573:7-12
references.pmid: 24796810
references.citation: Ann Neurol. 2005 Jul;58(1):147-50
references.pmid: 15984012
references.citation: Biochemistry. 2003 Nov 11;42(44):12749-60
references.pmid: 14596589
references.citation: Biochem Mol Biol Int. 1995 May;36(1):59-66
references.pmid: 7545052
references.citation: Nat Med. 2002 Nov;8(11):1263-9
references.pmid: 12379850
references.citation: Alzheimers Dement. 2013 Mar;9(2):99-112
references.pmid: 23375565
references.citation: J Mol Biol. 2004 May 21;339(1):145-59
references.pmid: 15123427
references.citation: J Alzheimers Dis. 2013;33(1):85-93
references.pmid: 22886024
references.citation: Biochemistry. 2000 Sep 5;39(35):10831-9
references.pmid: 10978169
references.citation: Ann Neurol. 2008 Mar;63(3):377-87
references.pmid: 18300294
references.citation: J Mass Spectrom. 2012 May;47(5):591-603
references.pmid: 22576872
references.citation: J Neurosci. 2011 May 18;31(20):7259-63
references.pmid: 21593310
references.citation: Am J Pathol. 2013 Aug;183(2):369-81
references.pmid: 23747948
references.citation: Proc Jpn Acad Ser B Phys Biol Sci. 2014;90(3):104-17
references.pmid: 24621957