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

ABSTRACT

BACKGROUND: The prion protein (PrP) is known to bind certain soluble aggregates of the amyloid ß-protein (Aß), 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. METHODS: Human 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 Aß. Since aqueous extracts of AD brain contain a complex mixture of active and inactive Aß species, we also assessed whether PrP-grafted antibodies could protect against neuritotoxicity mediated by AD brain-derived Aß. 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. RESULTS: Grafted antibodies bound a significant portion of aggregated Aß 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 Aß. CONCLUSIONS: These results further demonstrate that not all Aß oligomers are toxic and suggest that PrP derivatives may allow development of agents that differentially recognize toxic and innocuous Aß aggregates.