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 PrP^c-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. PrP^c 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 PrP^c 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 Aβ_42, 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-PrP^c mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer’s disease.

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LRP/LR Antibody Mediated Rescuing of Amyloid-β-Induced Cytotoxicity is Dependent on PrP c in Alzheimer’s Disease