PrP-grafted antibodies bind certain amyloid β-protein aggregates, but do not prevent toxicity

Abstract

BackgroundThe prion protein (PrP) is known to bind certain soluble aggregates of the amyloid β-protein (Aβ), and two regions of PrP, one centered around residues 19–33, and the other around 87–112, are thought to be particularly important for this interaction. When either of these sequences are grafted into a human IgG the resulting antibodies react with disease-associated PrP conformers, whereas the parental b12 IgG does not. MethodsHuman antibodies containing grafts of PrP 19–33 or 87–112 were prepared as before (Solforosi et al., 2007) and tested for their ability to recognize synthetic and Alzheimer’s disease (AD) brain-derived Aβ. Since aqueous extracts of AD brain contain a complex mixture of active and inactive Aβ species, we also assessed whether PrP-grafted antibodies could protect against neuritotoxicity mediated by AD brain-derived Aβ. For these experiments, human iPSC-derived neurons were grown in 96-well plates at 5000 cells per well and on post-induction day 21, AD brain extracts were added +/− test antibodies. Neurons were imaged for 3 days using an IncuCyte live-cell imaging system, and neurite number and density quantified. ResultsGrafted antibodies bound a significant portion of aggregated Aβ in aqueous AD extracts, but when these antibodies were co-incubated with neurons treated with brain extracts they did not reduce toxicity. By contrast, the PrP fragment N1 did protect against Aβ. ConclusionsThese results further demonstrate that not all Aβ oligomers are toxic and suggest that PrP derivatives may allow development of agents that differentially recognize toxic and innocuous Aβ aggregates.