title: A new motif in the N-terminal of acetylcholinesterase triggers amyloid-β aggregation and deposition.
abstract: OBJECTIVE
  As a molecular chaperone, acetylcholinesterase (AChE; EC 3.1.1.7) plays a critical role in the pathogenesis of Alzheimer's disease (AD). The peripheral anionic site (PAS) of AChE has been indicated as the amyloid-β (Aβ) binding domain. The goal of this study was to determine other motifs in AChE involved in Aβ aggregation and deposition.
  
  
  RESULTS
  The β-hairpin in monomeric Aβ is the key motif of nucleation-dependent Aβ self-aggregation. As AChE could induce Aβ aggregation and deposition, we searched AChE for β-hairpin structures. In A11-specific dot blot assay, AChE was detected by an oligomer-specific antibody A11, implying the existence of β-hairpin structures in AChE as β-hairpin was the core motif of oligomers. A molecular superimposing approach further revealed that the N-terminal region, from Glu7 to Ile20, in AChE (AChE 7-20) was similar to the β-hairpin domain in Aβ. The results of further dot blot assays, thioflavin T fluorescence assays, and electron microscopy imaging experiments, indicated that the N-terminal synthetic peptide AChE7-20 had nearly the same ability as AChE with regard to triggering Aβ aggregation and deposition.
  
  
  CONCLUSIONS
  AChE 7-20, a β-hairpin region in AChE, might be a new motif in AChE capable of triggering Aβ aggregation and deposition. This finding will be helpful to design new and more effective Aβ aggregation inhibitors for AD treatment.
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors: Li-Na
authors: LN
authors: Hou
authors: Jian-Rong
authors: JR
authors: Xu
authors: Qing-Nan
authors: QN
authors: Zhao
authors: Xiao-Ling
authors: XL
authors: Gao
authors: Yong-Yao
authors: YY
authors: Cui
authors: Jun
authors: J
authors: Xu
authors: Hao
authors: H
authors: Wang
authors: Hong-Zhuan
authors: HZ
authors: Chen
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000235:genetics; D020816:Amino Acid Motifs; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002942:Circular Dichroism; D005470:Fluorometry; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D008854:Microscopy, Electron; D008958:Models, Molecular; D058225:Plaque, Amyloid / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D058851:GPI-Linked Proteins; C548244:ACHE protein, human; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Alzheimer's disease; Amyloid-β; Oligomer
references: Am J Pathol. 2009 Nov;175(5):2121-32
references: 19834064
references: Nat Protoc. 2006;1(5):2406-15
references: 17406484
references: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5099-104
references: 18375754
references: Biochem Biophys Res Commun. 1997 Mar 27;232(3):652-5
references: 9126330
references: J Med Chem. 2012 Nov 26;55(22):10282-6
references: 23035744
references: Expert Opin Investig Drugs. 2011 Sep;20(9):1243-61
references: 21810032
references: Am J Pathol. 2004 Jun;164(6):2163-74
references: 15161650
references: J Med Chem. 2010 May 27;53(10):4002-8
references: 20408548
references: Neuron. 1996 Apr;16(4):881-91
references: 8608006
references: Science. 2006 Nov 3;314(5800):777-81
references: 17082447
references: CNS Neurosci Ther. 2010 Aug;16(4):235-45
references: 20560995
references: Biochemistry. 2003 Sep 16;42(36):10863-73
references: 12962511
references: Nature. 2004 Aug 5;430(7000):631-9
references: 15295589
references: J Neurochem. 1996 Apr;66(4):1335-46
references: 8627284
references: Curr Alzheimer Res. 2005 Jul;2(3):291-300
references: 15974894
references: Lancet. 1997 Jul 12;350(9071):134-8
references: 9228977
references: FEBS Lett. 1999 May 7;450(3):205-9
references: 10359075
references: Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9031-5
references: 8415649
references: PLoS One. 2008 Sep 18;3(9):e3235
references: 18800165
references: Acta Neuropathol. 1990;80(6):624-8
references: 1703383
references: Biochemistry. 2002 Nov 19;41(46):13539-47
references: 12427014
references: Crit Rev Biochem Mol Biol. 1997;32(5):361-404
references: 9383610
references: J Med Chem. 2008 Apr 10;51(7):2027-36
references: 18333606
references: Nat Neurosci. 2005 Jan;8(1):79-84
references: 15608634
references: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14126-31
references: 12391326
references: Acta Neuropathol. 1993;85(4):362-9
references: 8480510
references: Protein Sci. 2011 Jul;20(7):1114-8
references: 21594947
references: Physiol Rev. 2001 Apr;81(2):741-66
references: 11274343
references: J Biophotonics. 2011 Sep;4(9):637-44
references: 21702084
references: Lancet. 2005 Dec 17;366(9503):2112-7
references: 16360788
references: J Biol Chem. 2002 Oct 4;277(40):36948-54
references: 12149256
references: Curr Alzheimer Res. 2010 Aug;7(5):428-38
references: 20043808
references: J Neural Transm Suppl. 1990;30:13-23
references: 2391513
references: Eur J Med Chem. 2011 Jun;46(6):2609-16
references: 21497959
references: Neurobiol Aging. 2012 Nov;33(11):2641-60
references: 22305478
references: Science. 1987 Feb 27;235(4792):1046-9
references: 2950591