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Article type: Research Article
Authors: Pinnock, Emma C.a; 1 | Jovanovic, Katarinaa; 1 | Pinto, Maxine G.a | Ferreira, Eloisea | Dias, Bianca Da Costaa | Penny, Clementb | Knackmuss, Stefanc | Reusch, Uwec | Little, Melvync | Schatzl, Hermann M.d | Weiss, Stefan F.T.a; *
Affiliations: [a] School of Molecular and Cell Biology, University of the Witwatersrand, Wits, Johannesburg, Republic of South Africa (RSA) | [b] Department of Internal Medicine, University of the Witwatersrand, Johannesburg, Parktown, Republic of South Africa (RSA) | [c] Affimed GmbH, Technologiepark, Heidelberg, Germany | [d] Department of Comparative Biology & Experimental Medicine, University of Calgary, Calgary, AB, Canada
Correspondence: [*] Correspondence to: Stefan F.T. Weiss, School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, Republic of South Africa (RSA). Tel.: +2711717 6346; Fax: +27 11 7176351; E-mail: [email protected]
Note: [1] These authors contributed equally to this work.
Abstract: 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.
Keywords: Alzheimer’s disease, amyloid-β (Aβ), Cellular prion protein (PrPc), 37kDa/67kDa laminin receptor (LRP/LR)
DOI: 10.3233/JAD-150482
Journal: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 645-657, 2016
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