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

Mengel, D; Hong, W; Corbett, GT; Liu, W; DeSousa, A; Solforosi, L; Fang, C; ... Walsh, DM; + view all (2019) PrP-grafted antibodies bind certain amyloid β-protein aggregates, but do not prevent toxicity. Brain Research , 1710 pp. 125-135. 10.1016/j.brainres.2018.12.038. Green open access

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Abstract

BACKGROUND: The 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. 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 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. RESULTS: Grafted 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, PrP and the PrP fragment N1 did protect against Aβ. CONCLUSIONS: These 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.

Type: Article
Title: PrP-grafted antibodies bind certain amyloid β-protein aggregates, but do not prevent toxicity
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.brainres.2018.12.038
Publisher version: https://doi.org/10.1016/j.brainres.2018.12.038
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Alzheimer’s disease, Prion protein, Neuritotoxicity
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10066183
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