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-beta (A beta) neuritic plaques, composed predominantly of the neurotoxic A beta(42) isoform. Although the plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to solubleA beta(42) oligomers. The 37kDa/67kDa laminin receptor has been implicated in A beta(42) shedding and A beta(42)-induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and A beta(42), the mechanism underlying this cytotoxicity may be indirectly due to the PrPc-A beta(42) 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 A beta(42) cytotoxicity in vitro, while PrP(-/-)cells were more resistant to the cytotoxic effects of A beta(42) 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 A beta(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 A beta(42)-PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer's disease.