title: Anti-LRP/LR specific antibodies and shRNAs impede amyloid beta shedding in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is the most prevalent form of dementia. The amyloid beta (Aβ) peptide is the predominant candidate aetiological agent and is generated through the sequential proteolytic cleavage of the Amyloid Precursor Protein (APP) by beta (β) and gamma (γ) secretases. Since the cellular prion protein (PrP(c)) has been shown to regulate Aβ shedding, we investigated whether the cellular receptor for PrP(c), namely the 37 kDa/67 kDa Laminin Receptor (LRP/LR) played a role in Aβ shedding. Here we show that LRP/LR co-localises with the AD relevant proteins APP, β- and γ-secretase, respectively. Antibody blockage and shRNA knock-down of LRP/LR reduces Aβ shedding, due to impediment of β-secretase activity, rather than alteration of APP, β- and γ-secretase levels. These findings indicate that LRP/LR contributes to Aβ shedding and recommend anti-LRP/LR specific antibodies and shRNAs as novel therapeutic tools for AD treatment.
authors.affiliation: School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, Republic of South Africa.
authors.forename: Katarina
authors.initials: K
authors.lastname: Jovanovic
authors.forename: Danielle
authors.initials: D
authors.lastname: Gonsalves
authors.forename: Bianca
authors.initials: B
authors.lastname: Da Costa Dias
authors.forename: Kiashanee
authors.initials: K
authors.lastname: Moodley
authors.forename: Uwe
authors.initials: U
authors.lastname: Reusch
authors.forename: Stefan
authors.initials: S
authors.lastname: Knackmuss
authors.forename: Clement
authors.initials: C
authors.lastname: Penny
authors.forename: Marc S
authors.initials: MS
authors.lastname: Weinberg
authors.forename: Melvyn
authors.initials: M
authors.lastname: Little
authors.forename: Stefan F T
authors.initials: SF
authors.lastname: Weiss
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D017474:Receptors, Laminin / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D034741:RNA, Small Interfering; D017474:Receptors, Laminin; D053829:Amyloid Precursor Protein Secretases
references.citation: J Biol Chem. 2012 Nov 9;287(46):38408-25
references.pmid: 22988240
references.citation: EMBO J. 2001 Nov 1;20(21):5876-86
references.pmid: 11689428
references.citation: Nat Med. 1997 Dec;3(12):1383-8
references.pmid: 9396609
references.citation: J Alzheimers Dis. 2004 Feb;6(1):53-65
references.pmid: 15004328
references.citation: J Neurosci Res. 2000 Nov 1;62(3):451-62
references.pmid: 11054814
references.citation: Hum Mol Genet. 2012 Mar 1;21(5):1138-44
references.pmid: 22100763
references.citation: PLoS One. 2013 Jun 18;8(6):e66297
references.pmid: 23823499
references.citation: Prion. 2012 Jan-Mar;6(1):7-10
references.pmid: 22453170
references.citation: Cell Adhes Commun. 1994 Jul;2(3):201-9
references.pmid: 7827956
references.citation: Nat Cell Biol. 2003 May;5(5):486-8
references.pmid: 12679784
references.citation: J Infect Dis. 2006 Sep 1;194(5):702-9
references.pmid: 16897671
references.citation: Science. 1999 Oct 22;286(5440):735-41
references.pmid: 10531052
references.citation: PLoS One. 2013;8(3):e58888
references.pmid: 23554951
references.citation: Gene. 2011 Nov 15;488(1-2):1-12
references.pmid: 21699964
references.citation: Am J Pathol. 2005 Oct;167(4):1033-42
references.pmid: 16192638
references.citation: EMBO Rep. 2003 Mar;4(3):290-5
references.pmid: 12634848
references.citation: Neurodegener Dis. 2012;10(1-4):298-300
references.pmid: 22156337
references.citation: J Physiol Pharmacol. 2008 Dec;59 Suppl 9:217-35
references.pmid: 19261982
references.citation: Curr Protein Pept Sci. 2004 Feb;5(1):19-31
references.pmid: 14965318
references.citation: Nat Neurosci. 2012 Sep;15(9):1227-35
references.pmid: 22820466
references.citation: PLoS One. 2009 Nov 18;4(11):e7893
references.pmid: 19924286
references.citation: J Mol Biol. 2006 Apr 21;358(1):57-66
references.pmid: 16516231
references.citation: FEBS Lett. 2006 May 22;580(12):2922-7
references.pmid: 16529745
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E559-68
references.pmid: 21825135
references.citation: J Biol Chem. 2004 Oct 22;279(43):44945-54
references.pmid: 15322084
references.citation: Front Biosci (Landmark Ed). 2010 Jun 01;15:1150-63
references.pmid: 20515747
references.citation: J Biol Chem. 2005 Feb 11;280(6):4383-92
references.pmid: 15569674
references.citation: EMBO J. 2001 Nov 1;20(21):5863-75
references.pmid: 11689427
references.citation: Prion. 2011 Jul-Sep;5(3):126-37
references.pmid: 21862871
references.citation: Biochim Biophys Acta. 2008 May;1782(5):335-40
references.pmid: 18339329
references.citation: Nat Med. 2006 Jul;12(7):780-4
references.pmid: 16829947
references.citation: J Cell Sci. 2004 Oct 15;117(Pt 22):5437-45
references.pmid: 15466887
references.citation: Cold Spring Harb Perspect Med. 2012 Mar;2(3):a006312
references.pmid: 22393530
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11062-7
references.pmid: 17573534
references.citation: J Neurosci. 2008 Mar 12;28(11):2874-82
references.pmid: 18337418
references.citation: J Biol Chem. 2011 Sep 23;286(38):33489-500
references.pmid: 21795680
references.citation: Am J Physiol Cell Physiol. 2011 Apr;300(4):C723-42
references.pmid: 21209361
references.citation: J Cell Biol. 2003 Jan 6;160(1):113-23
references.pmid: 12515826
references.citation: J Mol Biol. 2008 May 2;378(3):530-9
references.pmid: 18387633
references.citation: Nature. 2009 Feb 26;457(7233):1128-32
references.pmid: 19242475
references.citation: PLoS One. 2013;8(3):e57409
references.pmid: 23472084
references.citation: Neuron. 1995 Apr;14(4):879-88
references.pmid: 7718249
references.citation: J Mol Biol. 2012 May 25;419(1-2):102-9
references.pmid: 22391421
references.citation: Expert Opin Ther Pat. 2011 Jan;21(1):35-53
references.pmid: 21110766
references.citation: PLoS One. 2010 Jul 27;5(7):e11820
references.pmid: 20676404
references.citation: J Biol Chem. 1997 Jan 24;272(4):2342-5
references.pmid: 8999943
references.citation: Sci Rep. 2013;3:2702
references.pmid: 24048171
references.citation: J Cell Sci. 2003 Aug 15;116(Pt 16):3339-46
references.pmid: 12829747