PrP-grafted antibodies bind certain amyloid β-protein aggregates, but do not prevent toxicity.
Alzheimer’s disease
Neuritotoxicity
Prion protein
Journal
Brain research
ISSN: 1872-6240
Titre abrégé: Brain Res
Pays: Netherlands
ID NLM: 0045503
Informations de publication
Date de publication:
01 05 2019
01 05 2019
Historique:
received:
04
09
2018
revised:
26
11
2018
accepted:
23
12
2018
pubmed:
30
12
2018
medline:
26
6
2020
entrez:
30
12
2018
Statut:
ppublish
Résumé
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. 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. 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, the PrP fragment N1 did protect against Aβ. 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.
Sections du résumé
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, 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.
Identifiants
pubmed: 30593771
pii: S0006-8993(18)30664-4
doi: 10.1016/j.brainres.2018.12.038
pmc: PMC6431553
mid: NIHMS1518007
pii:
doi:
Substances chimiques
Amyloid beta-Peptides
0
Antibodies
0
Prion Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
125-135Subventions
Organisme : NIA NIH HHS
ID : T32 AG000222
Pays : United States
Organisme : Medical Research Council
ID : MC_UP_1604/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00024/8
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : P30 AG062421
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG047505
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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