title: Active and passive immunization strategies based on the SDPM1 peptide demonstrate pre-clinical efficacy in the APPswePSEN1dE9 mouse model for Alzheimer's disease.
abstract: Recent clinical and pre-clinical studies suggest that both active and passive immunization strategies targeting Aβ amyloid may have clinical benefit in Alzheimer's disease. Here, we demonstrate that vaccination of APPswePSEN1dE9 mice with SDPM1, an engineered non-native Aβ amyloid-specific binding peptide, lowers brain Aβ amyloid plaque burden and brain Aβ1-40 and Aβ1-42 peptide levels, improves cognitive learning and memory in Morris water maze tests and increases the expression of synaptic brain proteins. This was the case in young mice immunized prior to development of significant brain amyloid burden, and in older mice, where brain amyloid was already present. Active immunization was optimized using ALUM as an adjuvant to stimulate production of anti-SDPM1 and anti-Aβ amyloid antibodies. Intracerebral injection of P4D6, an SDPM1 peptide-mimotope antibody, also lowered brain amyloid plaque burden in APPswePSEN1dE9 mice. Additionally, P4D6 inhibited Aβ amyloid-mediated toxicity in cultured neuronal cells. The protein sequence of the variable domain within the P4D6 heavy chain was found to mimic a multimer of the SDPM1 peptide motif. These data demonstrate the efficacy of active and passive vaccine strategies to target Aβ amyloid oligomers using an engineered peptide-mimotope strategy.
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA.
authors.forename: Marybeth
authors.initials: M
authors.lastname: Camboni
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA.
authors.forename: Chiou-Miin
authors.initials: CM
authors.lastname: Wang
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Miranda
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA.
authors.forename: Jung Hae
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Zygmunt
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA; Department of Pediatrics, The Ohio State University, USA; Department of Neuroscience, The Ohio State University, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA; Department of Pediatrics, The Ohio State University, USA; Department of Physiology and Cell Biology, The Ohio State University, USA. Electronic address: Paul.Martin@nationwidechildrens.org.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Martin
mesh_terms: D000536:Aluminum Hydroxide / Q000276:immunology; D000544:Alzheimer Disease / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D023582:Alzheimer Vaccines / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology; D007116:Immunization, Passive; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use*; D058225:Plaque, Amyloid / Q000473:pathology; D013569:Synapses / Q000378:metabolism; D016896:Treatment Outcome; D014611:Vaccination
chemical_list: D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C000591258:SDPM1 peptide; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D000536:Aluminum Hydroxide
keywords: Alzheimer's disease; Amyloid; Learning; Memory; Neurodegeneration; PSD95; Peptide mimotope; Synapse; Synaptophysin; Vaccine
references.citation: J Clin Invest. 2003 Aug;112(3):415-22
references.pmid: 12897209
references.citation: Neurology. 2010 Jun 15;74(24):2026; author reply 2026-7
references.pmid: 20548049
references.citation: Neuron. 1997 Oct;19(4):939-45
references.pmid: 9354339
references.citation: Ann Neurol. 1990 May;27(5):457-64
references.pmid: 2360787
references.citation: Vaccine. 2006 Mar 20;24(13):2275-82
references.pmid: 16368167
references.citation: Clin Neuropathol. 2007 Mar-Apr;26(2):43-58
references.pmid: 17416103
references.citation: J Nutr Health Aging. 2009 Mar;13(3):264-7
references.pmid: 19262965
references.citation: Neurology. 2005 May 10;64(9):1553-62
references.pmid: 15883316
references.citation: Neuromuscul Disord. 2003 Jun;13(5):365-75
references.pmid: 12798792
references.citation: Ann Neurol. 1991 Oct;30(4):572-80
references.pmid: 1789684
references.citation: Annu Rev Immunol. 2012;30:531-64
references.pmid: 22224781
references.citation: Am J Physiol Cell Physiol. 2003 May;284(5):C1309-18
references.pmid: 12676658
references.citation: J Neuropathol Exp Neurol. 2012 May;71(5):362-81
references.pmid: 22487856
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53
references.pmid: 9600986
references.citation: Nature. 1999 Jul 8;400(6740):173-7
references.pmid: 10408445
references.citation: Trends Immunol. 2009 Jul;30(7):351-9
references.pmid: 19540808
references.citation: Arch Neurol. 2012 Feb;69(2):198-207
references.pmid: 21987394
references.citation: Immunity. 2006 Jun;24(6):663-666
references.pmid: 16782020
references.citation: Nat Neurosci. 2010 Feb;13(2):190-6
references.pmid: 20037574
references.citation: Prog Brain Res. 2009;175:83-93
references.pmid: 19660650
references.citation: Neurobiol Dis. 2003 Oct;14(1):146-56
references.pmid: 13678675
references.citation: Adv Exp Med Biol. 2012;970:573-601
references.pmid: 22351073
references.citation: Alzheimers Dement. 2008 Jan;4(1 Suppl 1):S119-21
references.pmid: 18631987
references.citation: Neurobiol Dis. 2009 Nov;36(2):293-302
references.pmid: 19660551
references.citation: Science. 1992 Apr 10;256(5054):184-5
references.pmid: 1566067
references.citation: Am J Pathol. 1991 Jan;138(1):235-46
references.pmid: 1899001
references.citation: J Neuropathol Exp Neurol. 1996 Oct;55(10):1023-5
references.pmid: 8857998
references.citation: J Alzheimers Dis. 2011;24(2):315-25
references.pmid: 21263194
references.citation: Nature. 2002 Apr 4;416(6880):535-9
references.pmid: 11932745
references.citation: Nat Med. 2008 Aug;14(8):837-42
references.pmid: 18568035
references.citation: Neurology. 2003 Jul 8;61(1):46-54
references.pmid: 12847155
references.citation: Nat Rev Neurol. 2010 Feb;6(2):108-19
references.pmid: 20140000
references.citation: J Neuropathol Exp Neurol. 1997 Aug;56(8):933-44
references.pmid: 9258263
references.citation: Neuron. 2003 May 22;38(4):547-54
references.pmid: 12765607
references.citation: J Biol Chem. 2009 Mar 6;284(10):6033-7
references.pmid: 18948253
references.citation: J Neurosci. 2005 Oct 5;25(40):9096-101
references.pmid: 16207868
references.citation: Eur J Immunol. 2005 Mar;35(3):946-56
references.pmid: 15688346
references.citation: J Neurosci Res. 2008 Aug 1;86(10):2314-25
references.pmid: 18438916
references.citation: Nature. 2006 Mar 16;440(7082):352-7
references.pmid: 16541076
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8850-5
references.pmid: 11438712
references.citation: J Neurosci. 2009 Sep 9;29(36):11393-8
references.pmid: 19741145
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2023-8
references.pmid: 12566568
references.citation: Nat Neurosci. 2005 Jan;8(1):79-84
references.pmid: 15608634
references.citation: CNS Neurol Disord Drug Targets. 2010 Apr;9(2):207-16
references.pmid: 20205639
references.citation: Biomol Eng. 2001 Jun;17(6):157-65
references.pmid: 11337275
references.citation: J Clin Invest. 2006 Jan;116(1):193-201
references.pmid: 16341263
references.citation: Tohoku J Exp Med. 2010 Feb;220(2):95-106
references.pmid: 20139660
references.citation: J Neuroinflammation. 2006 May 10;3:11
references.pmid: 16686956
references.citation: Aging Clin Exp Res. 2009 Jun;21(3):201-9
references.pmid: 19571643
references.citation: Cell Differ. 1984 Jun;14(2):135-44
references.pmid: 6467378
references.citation: J Alzheimers Dis. 2001 Feb;3(1):75-80
references.pmid: 12214075
references.citation: J Neurosci. 2007 Mar 14;27(11):2866-75
references.pmid: 17360908
references.citation: Physiol Rev. 2001 Apr;81(2):741-66
references.pmid: 11274343
references.citation: FEBS J. 2010 Jul;277(14):3051-67
references.pmid: 20573181
references.citation: J Neuropathol Exp Neurol. 2006 Nov;65(11):1040-8
references.pmid: 17086100
references.citation: Neurobiol Dis. 2005 Apr;18(3):602-17
references.pmid: 15755686
references.citation: J Neurosci. 2003 May 1;23(9):3745-51
references.pmid: 12736345
references.citation: Neurology. 1992 Jan;42(1):115-9
references.pmid: 1734291
references.citation: Annu Rev Immunol. 1990;8:303-33
references.pmid: 1693082
references.citation: J Neurosci. 2001 Feb 15;21(4):1327-33
references.pmid: 11160403
references.citation: J Neurosci Res. 1994 Nov 1;39(4):377-85
references.pmid: 7533843
references.citation: Immunotherapy. 2012 Feb;4(2):213-38
references.pmid: 22339463
references.citation: Neurodegener Dis. 2008;5(3-4):194-6
references.pmid: 18322388
references.citation: J Mol Cell Biol. 2012 Feb;4(1):29-37
references.pmid: 22158907
references.citation: Mol Cell Neurosci. 2009 Aug;41(4):448-63
references.pmid: 19442736
references.citation: J Neurochem. 2012 Jan;120 Suppl 1:186-193
references.pmid: 21883222
references.citation: Neurobiol Aging. 2003 Dec;24(8):1029-46
references.pmid: 14643375
references.citation: J Neurochem. 2005 Nov;95(3):834-47
references.pmid: 16135089
references.citation: Biochemistry. 2007 Nov 13;46(45):13049-58
references.pmid: 17944486
references.citation: J Neuroimmunol. 2011 Jul;236(1-2):27-38
references.pmid: 21641049
references.citation: J Neurosci. 2006 Nov 15;26(46):11923-8
references.pmid: 17108166
references.citation: Am J Pathol. 2000 Oct;157(4):1239-46
references.pmid: 11021828
references.citation: Expert Rev Vaccines. 2011 Apr;10(4):539-50
references.pmid: 21506650
references.citation: Neurobiol Dis. 2010 Sep;39(3):409-22
references.pmid: 20493257
references.citation: J Neurosci. 2002 Dec 15;22(24):10539-48
references.pmid: 12486146
references.citation: Neuron. 2006 Dec 7;52(5):831-43
references.pmid: 17145504