The neuronal perturbations in Alzheimer’s disease are attributed to the formation of extracellular amyloid-β (Aβ) neuritic plaques, composed predominantly of the neurotoxic Aβ42 isoform. Although the plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to soluble Aβ42 oligomers. The 37kDa/67kDa laminin receptor has been implicated in Aβ42 shedding and Aβ42-induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and Aβ42, the mechanism underlying this cytotoxicity may be indirectly due to the PrPc-Aβ42 interaction with LRP/LR. The effects of this interaction were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assays. PrPc overexpression significantly enhanced Aβ42 cytotoxicity in vitro, while PrP–/– cells were more resistant to the cytotoxic effects of Aβ42 and exhibited significantly less cell death than PrPc expressing N2a cells. Although anti-LRP/LR specific antibody IgG1-iS18 significantly enhanced cell viability in both pSFV1-huPrP1-253 transfected and non-transfected cells treated with exogenous Aβ42, it failed to have any cell rescuing effect in PrP–/– HpL3-4 cells. These results suggest that LRP/LR plays a significant role in Aβ42-PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer’s disease.
VerdierYPenkeB2004Binding sites of amyloid beta-peptide in cell plasma membrane and implications for Alzheimer’s diseaseCurr Protein Pept Sci51931
2.
Serrano-PozoAFroschMPMasliahEHymanBT2011Neuropathological alterations in Alzheimer diseaseCold Spring Harb Perspect Med1a006189
3.
XiaoYMaBMcElhenyDParthasarathySLongFHoshiMNussinovRIshiiY2015Abeta(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer’s diseaseNat Struct Mol Biol22499505
4.
DicksonDW1997Discovery of new lesions in neurodegenerative diseases with monoclonal antibody techniques: Is there a non-amyloid precursor to senile plaques?Am J Pathol151711
5.
CaetanoFABeraldoFHHajjGNGuimaraesALJurgensenSWasilewska-SampaioAPHirataPHSouzaIMachadoCFWongDYDe FeliceFGFerreiraSTPradoVFRylettRJMartinsVRPradoMA2011Amyloid-beta oligomers increase the localization of prion protein at the cell surfaceJ Neurochem117538553
6.
KakiyaNSaitoTNilssonPMatsubaYTsubukiSTakeiNNawaHSaidoTC2012Cell surface expression of the major amyloid-beta peptide (Abeta)-degrading enzyme, neprilysin, depends on phosphorylation by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) and dephosphorylation by protein phosphatase 1aJ Biol Chem2872936229372
7.
ClearyJPWalshDMHofmeisterJJShankarGMKuskowskiMASelkoeDJAsheKH2005Natural oligomers of the amyloid-beta protein specifically disrupt cognitive functionNat Neurosci87984
8.
JangBGInSChoiBKimMJ2014Beta-amyloid oligomers induce early loss of presynaptic proteins in primary neurons by caspase-dependent and proteasome-dependent mechanismsNeuroreport2512811288
9.
ChoiSHKimYHHebischMSliwinskiCLeeSD’AvanzoCChenHHooliBAsselinCMuffatJKleeJBZhangCWaingerBJPeitzMKovacsDMWoolfCJWagnerSLTanziREKimDY2014A three-dimensional human neural cell culture model of Alzheimer’s diseaseNature515274278
10.
MuckeLSelkoeDJ2012Neurotoxicity of amyloid beta-protein: Synatic and network dysfunctionCold Spring Harb Perspect Med2a006338
11.
KamTIGwonYJungYK2014Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimer’s diseaseCell Mol Life Sci7148034813
12.
LinHBhatiaRLalR2001Amyloid beta protein forms ion channels: Implications for Alzheimer’s disease pathophysiologyFASEB J1524332444
13.
DemuroAMinaEKayedRMiltonSCParkerIGlabeCG2005Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomersJ Biol Chem2801729417300
14.
StefaniM2010Biochemical and biophysical features of both oligomer/fibril and cell membrane in amyloid cytotoxicityFEBS J27746024613
15.
BarryAEKlyubinIMcDonaldJMMablyAJFarrellMAScottMWalshDMRowanMJ2011Alzheimer’sdisease brain-derived amyloid-beta-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion proteinJ Neurosci3172597263
16.
LaurenJGimbelDANygaardHBGilbertJWStrittmatterSM2009Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomersNature45711281132
17.
DohlerFSepulveda-FallaDKrasemannSAltmeppenHSchluterHHildebrandDZerrIMatschkeJGlatzelM2014High molecular mass assemblies of amyloid-beta oligomers bind prion protein in patients with Alzheimer’s diseaseBrain137873886
18.
PetersCEspinozaMPGallegosSOpazoCAguayoLG2015Alzheimer’s Abeta interacts with cellular prion protein inducing neuronal membrane damage and synaptotoxicityNeurobiol Aging3613691377
19.
ParkinETWattNTHussainIEckmanEAEckmanCBMansonJCBaybuttHNTurnerAJHooperNM2007Cellular prion protein regulates beta-secretase cleavage of the Alzheimer’s amyloid precursor proteinProc Natl Acad SciU S A1041106211067
20.
GauczynskiSPeyrinJMHaikSLeuchtCHundtCRiegerRKrasemannSDeslysJPDormontDLasmezasCIWeissS2001The 37-kDa/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion proteinEMBO J2058635875
21.
MbazimaVDa Costa DiasBOmarAJovanovicKWeissS2010Interactions between PrPc and other ligands with the 37-kDa/67-kDa laminin receptorFront Biosci1511501163
22.
OmarAJovanovicKDa Costa DiasBGonsalvesDMoodleyKCaveneyRMbazimaVWeissSF2011Patented biological approaches for the therapeutic modulation of the 37 kDa/67 kDa laminin receptorExpert Opin Ther Pat213553
23.
HundtCPeyrinJMHaikSGauczynskiSLeuchtCRiegerRRileyMLDeslysJPDormontDLasmezasCIWeissS2001Identification of interaction domains of the prion protein with its 37-kDa/67-kDa laminin receptorEMBO J2058765886
24.
DiGiacomoVMerueloD2015Looking into laminin receptor: Critical discussion regarding the non-integrin 37/67-kDa laminin receptor/RPSA proteinBiol Rev Camb Philos Soc10.1111/brv.12170
25.
JovanovicKChettyCJKhumaloTDa Costa DiasBFerreiraEMalindisaSTCaveneyRLetsoloBTWeissSF2015Novel patented therapeutic approaches targeting the 37/67 kDa laminin receptor for treatment of cancer and Alzheimer’s diseaseExpert Opin Ther Pat25567582
26.
ZuberCKnackmussSZemoraGReuschUVlasovaEDiehlDMickVHoffmannKNiklesDFrohlichTArnoldGJBrenigBWolfELahmHLittleMWeissS2008Invasion of tumorigenic HT1080 cells is impeded by blocking or downregulating the 37-kDa/67-kDa laminin receptorJ Mol Biol378530539
27.
ChettyCKhumaloTDa Costa DiasBReuschUKnackmussSLittleMWeissSF2014Anti-LRP/LR specific antibody IgG1-iS18 impedes adhesion and invasion of liver cancer cellsPLoS One9e96268
28.
KhumaloTReuschUKnackmussSLittleMVealeRBWeissSF2013Adhesion and invasion of breast and oesophageal cancer cells are impeded by Anti-LRP/LR-specific antibody IgG1-iS18PLoS One8e66297
29.
OmarAReuschUKnackmussSLittleMWeissSF2012Anti-LRP/LR-specific antibody IgG1-iS18 significantly reduces adhesion and invasion of metastatic lung, cervix, colon and prostate cancer cellsJ Mol Biol419102109
30.
KhusalRDa Costa DiasBMoodleyKPennyCReuschUKnackmussSLittleMWeissSF2013In vitro inhibition of angiogenesis by antibodies directed against the 37kDa/67kDa laminin receptorPLoS One8e58888
31.
NarindrasorasakSLoweryDEAltmanRAGonzalez-DeWhittPAGreenbergBDKisilevskyR1992Characterization of high affinity binding between laminin and Alzheimer’s disease amyloid precursor proteinsLab Invest67643652
32.
JovanovicKGonsalvesDDias BdaCMoodleyKReuschUKnackmussSPennyCWeinbergMSLittleMWeissSF2013Anti-LRP/LR specific antibodies and shRNAs impede amyloid beta shedding in Alzheimer’s diseaseSci Rep32699
33.
JovanovicKLoosBDa Costa DiasBPennyCWeissSF2014High Resolution Imaging Study of Interactions between the 37 kDa/67 kDa laminin receptor and APP, Beta-Secretase and Gamma-secretase in Alzheimer’s diseasePLoS One9e100373
34.
Da Costa DiasBJovanovicKGonsalvesDMoodleyKReuschUKnackmussSWeinbergMSLittleMWeissSFT2014The 37kDa/67kDa laminin receptor acts as a receptor for Abeta42 internalizationSci Rep45556
35.
Da Costa DiasBJovanovicKGonsalvesDMoodleyKReuschUKnackmussSPennyCWeinbergMSLittleMWeissSF2013Anti-LRP/LR specific antibody IgG1-iS18 and knock-down of LRP/LR by shRNAs rescue cells from Abeta42 induced cytotoxicitySci Rep32702
36.
SakudoAOnoderaTSuganumaYKobayashiTSaekiKIkutaK2006Recent advances in clarifying prion protein functions using knockout mice and derived cell linesMini Rev Med Chem6589601
MaasEGeissenMGroschupMHRostROnoderaTSchätzlHVorbergIM2007Scrapie infection of prion protein-deficient cell line upon ectopic expression of mutant prion proteinsJ Biol Chem2821870218710
39.
GauczynskiSNiklesDEl-GogoSPapy-GarciaDReyCAlbanSBarritaultDLasmezasCIWeissS2006The 37-kDa/67-kDa laminin receptor acts as a receptor for infectious prions and is inhibited by polysulfated glycanesJ Infect Dis194702709
40.
UmJWNygaardHBHeissJKKostylevMAStagiMVortmeyerAWisniewskiTGuntherECStrittmatterSM2012Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neuronsNat Neurosci1512271235
41.
NygaardHBvan DyckCHStrittmatterSM2014Fyn kinase inhibition as a novel therapy for Alzheimer’s diseaseAlzheimers Res Ther68
42.
YouHTsutsuiSHameedSKannanayakalTJChenLXiaPEngbersJDLiptonSAStysPKZamponiGW2012Abeta neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptorsProc Natl Acad Sci U S A10917371742
43.
UmJWKaufmanACKostylevMHeissJKStagiMTakahashiHKerriskMEVortmeyerAWisniewskiTKoleskeAJGuntherECNygaardHBStrittmatterSM2013Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer abeta oligomer bound to cellular prion proteinNeuron79887902
44.
RushworthJVGriffithsHHWattNTHooperNM2013Prion protein-mediated toxicity of amyloid-beta oligomers requires lipid rafts and the transmembrane LRP1J Biol Chem28889358951
45.
YounanNDSarellCJDaviesPBrownDRVilesJH2013The cellular prion protein traps Alzheimer’s Abeta in an oligomeric form and disassembles amyloid fibersFASEB J2718471858
46.
KolodziejczakDDa Costa DiasBZuberCJovanovicKOmarABeckJVanaKMbazimaVRichtJBrenigBWeissSF2010Prion interaction with the 37-kDa/67-kDa laminin receptor on enterocytes as a cellular model for intestinal uptake of prionsJ Mol Biol402293300
47.
LiFChenXWangFXuSChangLAnwylRWangQ2013Chronic pre-treatment with memantine prevents amyloid-beta protein mediated long-term potentiation disruptionNeural Regen Res84955
48.
CizasPJekabsoneABorutaiteVMorkunieneR2011Prevention of amyloid-beta oligomer-induced neuronal death by EGTA, estradiol, and endocytosis inhibitorMedicina(Kaunas)47107112
49.
WalshDMKlyubinIShankarGMTownsendMFadeevaJVBettsVPodlisnyMBClearyJPAsheKHRowanMJSelkoeDJ2005The role of cell-derived oligomers of Abeta in Alzheimer’s disease and avenues for therapeutic interventionBiochem Soc Trans3310871090
50.
KesselsHWNguyenLNNabaviSMalinowR2010The prion protein as a receptor for amyloid-betaNature466E3E4discussion E4-5.
51.
CalellaAMFarinelliMNuvoloneMMiranteOMoosRFalsigJMansuyIMAguzziA2010Prion protein and Abeta-related synaptic toxicity impairmentEMBO Mol Med2306314
52.
CisseMSanchezPEKimDHHoKYuGQMuckeL2011Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic miceJ Neurosci311042710431
53.
MorelEAndrieuTCasagrandeFGauczynskiSWeissSGrassiJRoussetMDormontDChambazJ2005Bovine prion is endocytosed by human enterocytes via the 37 kDa/67 kDa laminin receptorAm J Pathol16710331042
54.
FreirDBNicollAJKlyubinIPanicoSMc DonaldJMRisseEAsanteEAFarrowMASessionsRBSaibilHRClarkeARRowanMJWalshDMCollingeJ2011Interaction between prion protein and toxic amyloid beta assemblies can be therapeutically targeted at multiple sitesNat Commun2336
