LRP/LR Antibody Mediated Rescuing of Amyloid-β-Induced Cytotoxicity is Dependent on PrPc in Alzheimer's Disease.
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.
School of Molecular and Cell Biology, University of the Witwatersrand, Wits, Johannesburg, Republic of South Africa (RSA).
Emma C
EC
Pinnock
School of Molecular and Cell Biology, University of the Witwatersrand, Wits, Johannesburg, Republic of South Africa (RSA).
Katarina
K
Jovanovic
School of Molecular and Cell Biology, University of the Witwatersrand, Wits, Johannesburg, Republic of South Africa (RSA).
Maxine G
MG
Pinto
School of Molecular and Cell Biology, University of the Witwatersrand, Wits, Johannesburg, Republic of South Africa (RSA).
Eloise
E
Ferreira
School of Molecular and Cell Biology, University of the Witwatersrand, Wits, Johannesburg, Republic of South Africa (RSA).
Bianca Da Costa
Bda C
Dias
Department of Internal Medicine, University of the Witwatersrand, Johannesburg, Parktown, Republic of South Africa (RSA).
Clement
C
Penny
Affimed GmbH, Technologiepark, Heidelberg, Germany.
Stefan
S
Knackmuss
Affimed GmbH, Technologiepark, Heidelberg, Germany.
Uwe
U
Reusch
Affimed GmbH, Technologiepark, Heidelberg, Germany.
Melvyn
M
Little
Department of Comparative Biology & Experimental Medicine, University of Calgary, Calgary, AB, Canada.
Hermann M
HM
Schatzl
School of Molecular and Cell Biology, University of the Witwatersrand, Wits, Johannesburg, Republic of South Africa (RSA).
Stefan F T
SF
Weiss
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D017474:Receptors, Laminin / Q000276:immunology*; D012269:Ribosomal Proteins; D014162:Transfection
D016229:Amyloid beta-Peptides; D000906:Antibodies; D010446:Peptide Fragments; D011328:Prions; C510624:RPSA protein, human; D017474:Receptors, Laminin; D012269:Ribosomal Proteins; C075222:amyloid beta-protein (1-42)
37kDa/67kDa laminin receptor (LRP/LR); Alzheimer’s disease; Cellular prion protein (PrPc); amyloid-β (Aβ)