title: Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation.
abstract: The amyloid-forming proteins tau, αB crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein αB crystallin (HspB5) and from amyloid β fibrils, characteristic of Alzheimer's disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, we showed a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid β A4, major prion protein (PrP), HspB5, amylin, serum amyloid P, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-6 and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of tau 623-628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305-5316, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kurnellas
authors.forename: Chris M
authors.initials: CM
authors.lastname: Adams
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Rothbard
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D052160:Benzothiazoles; D019921:Biotinylation / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D011232:Chemical Precipitation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism; D008969:Molecular Sequence Data; D009420:Nervous System / Q000187:drug effects / Q000473:pathology*; D010243:Paralysis / Q000097:blood / Q000150:complications / Q000188:drug therapy; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D055503:Protein Multimerization / Q000187:drug effects; D013844:Thiazoles / Q000378:metabolism
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D001798:Blood Proteins; D015850:Interleukin-6; D018832:Molecular Chaperones; D010455:Peptides; D013844:Thiazoles; C009462:thioflavin T
references.citation: J Alzheimers Dis. 2012;28(2):369-75
references.pmid: 22002789
references.citation: Sci Transl Med. 2012 Aug 1;4(145):145ra105
references.pmid: 22855462
references.citation: Science. 2012 Mar 9;335(6073):1228-31
references.pmid: 22403391
references.citation: Nat Biotechnol. 2007 Jan;25(1):61-2
references.pmid: 17211399
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9041-6
references.pmid: 18577591
references.citation: J Biol Chem. 2012 Oct 26;287(44):37206-18
references.pmid: 22918834
references.citation: Biochemistry. 1993 May 11;32(18):4693-7
references.pmid: 8490014
references.citation: Glia. 2012 May;60(6):993-1003
references.pmid: 22438044
references.citation: Biochem J. 1949;44(1):126-8
references.pmid: 16748471
references.citation: Nat Immunol. 2010 Oct;11(10):897-904
references.pmid: 20835230
references.citation: Biophys J. 2010 Mar 3;98(5):843-51
references.pmid: 20197038
references.citation: Science. 2008 Mar 14;319(5869):1523-6
references.pmid: 18339938
references.citation: Eye (Lond). 2011 Jun;25(6):809-17
references.pmid: 21475310
references.citation: J Immunol. 2011 Jul 1;187(1):64-73
references.pmid: 21622869
references.citation: PLoS Biol. 2012;10(6):e1001346
references.pmid: 22723742
references.citation: J Neuropathol Exp Neurol. 2012 May;71(5):422-33
references.pmid: 22487860
references.citation: Nature. 2007 May 24;447(7143):453-7
references.pmid: 17468747
references.citation: J Mol Biol. 2010 Dec 17;404(5):917-34
references.pmid: 20970427
references.citation: Nat Chem Biol. 2009 Jan;5(1):15-22
references.pmid: 19088715
references.citation: J Biol Chem. 2009 Dec 4;284(49):34272-82
references.pmid: 19808677
references.citation: Nat Immunol. 2008 Aug;9(8):857-65
references.pmid: 18604209
references.citation: Biochemistry. 2001 May 22;40(20):6036-46
references.pmid: 11352739
references.citation: J Proteome Res. 2006 Nov;5(11):2909-18
references.pmid: 17081042
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3487-92
references.pmid: 20133726
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13287-92
references.pmid: 21828004
references.citation: J Biol Chem. 2012 Oct 19;287(43):36423-34
references.pmid: 22955287
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7
references.pmid: 16293696
references.citation: Mult Scler. 2003 Oct;9(5):476-80
references.pmid: 14582773
references.citation: Mol Med. 1995 Nov;1(7):795-805
references.pmid: 8612202
references.citation: Biochem J. 1993 Jul 1;293 ( Pt 1):27-30
references.pmid: 8328966
references.citation: J Neurochem. 2012 Jul;122(1):208-20
references.pmid: 22519988
references.citation: Biochemistry. 2008 Mar 4;47(9):2961-7
references.pmid: 18232642
references.citation: Science. 2003 Apr 18;300(5618):486-9
references.pmid: 12702875
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13003-8
references.pmid: 11087855
references.citation: Ann Neurol. 2006 Jul;60(1):12-21
references.pmid: 16802293
references.citation: Immunol Cell Biol. 2012 Apr;90(4):388-95
references.pmid: 21647172
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4074-8
references.pmid: 16537487
references.citation: Biochemistry. 2006 Aug 1;45(30):9342-53
references.pmid: 16866381
references.citation: Cell. 1993 Jun 18;73(6):1055-8
references.pmid: 8513491
references.citation: Biochemistry. 2005 Dec 20;44(50):16701-9
references.pmid: 16342960
references.citation: Methods Enzymol. 2006;413:273-312
references.pmid: 17046402
references.citation: Nature. 2008 Feb 28;451(7182):1076-81
references.pmid: 18278032
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81
references.pmid: 8446617
references.citation: Biophys J. 2011 Oct 5;101(7):1681-9
references.pmid: 21961594
references.citation: Biochem Biophys Res Commun. 2011 Dec 9;416(1-2):130-4
references.pmid: 22100649
references.citation: Nature. 2007 Jul 26;448(7152):474-9
references.pmid: 17568699
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10427-32
references.pmid: 16020533
references.citation: Cell. 2012 Mar 16;148(6):1188-203
references.pmid: 22424229
references.citation: J Biol Chem. 2012 Mar 23;287(13):9708-9721
references.pmid: 22308023
references.citation: J Neuroinflammation. 2012 Jan 26;9:25
references.pmid: 22281016
references.citation: Ann Thorac Surg. 2011 Jun;91(6):1907-13
references.pmid: 21619989
references.citation: Proc Natl Acad Sci U S A. 2012 May 15;109(20):7717-22
references.pmid: 22547798
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14948-53
references.pmid: 19706421