ABSTRACT
The neuronal perturbations in Alzheimer's disease are attributed to the formation of extracellular amyloid-ß (Aß) neuritic plaques, composed predominantly of the neurotoxic Aß42 isoform. Although the plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to soluble Aß42 oligomers. The 37kDa/67kDa laminin receptor has been implicated in Aß42 shedding and Aß42-induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and Aß42, the mechanism underlying this cytotoxicity may be indirectly due to the PrPc-Aß42 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 Aß42 cytotoxicity in vitro, while PrP-/- cells were more resistant to the cytotoxic effects of Aß42 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 Aß42, it failed to have any cell rescuing effect in PrP-/- HpL3-4 cells. These results suggest that LRP/LR plays a significant role in Aß42-PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer's disease.
