Title | LRP/LR Antibody Mediated Rescuing of Amyloid-β-Induced Cytotoxicity is Dependent on PrPc in Alzheimer's Disease. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Pinnock, EC, Jovanovic, K, Pinto, MG, Ferreira, E, Dias, BDa Costa, Penny, C, Knackmuss, S, Reusch, U, Little, M, Schatzl, HM, Weiss, SFT |
Journal | J Alzheimers Dis |
Volume | 49 |
Issue | 3 |
Pagination | 645-57 |
Date Published | 2016 |
ISSN | 1875-8908 |
Keywords | Amyloid beta-Peptides, Animals, Antibodies, Cell Line, Transformed, Cell Survival, Flow Cytometry, Gene Expression Regulation, Humans, Mice, Peptide Fragments, Prions, Receptors, Laminin, Transfection |
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. |
DOI | 10.3233/JAD-150482 |
Alternate Journal | J. Alzheimers Dis. |
PubMed ID | 26484914 |