Conformation-specific antibodies against multiple amyloid protofibril species from a single amyloid immunogen.
Alzheimer Disease
/ immunology
Amyloid
/ immunology
Amyloid beta-Peptides
/ immunology
Animals
Antibodies, Monoclonal
/ chemistry
Antibody Specificity
/ immunology
Brain
/ immunology
Epitopes
/ chemistry
Humans
Islet Amyloid Polypeptide
/ immunology
Mice
Nucleobindins
/ immunology
Peptide Fragments
/ immunology
Protein Binding
Protein Conformation
Pyramidal Cells
/ immunology
Alzheimer’s disease
amyloid
amyloid aggregation
chaperone-like amyloid-binding protein
conformation-sensitive
monoclonal antibody
protofibril
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
21
09
2018
revised:
28
11
2018
accepted:
07
12
2018
pubmed:
22
1
2019
medline:
8
7
2020
entrez:
22
1
2019
Statut:
ppublish
Résumé
We engineered and employed a chaperone-like amyloid-binding protein Nucleobindin 1 (NUCB1) to stabilize human islet amyloid polypeptide (hIAPP) protofibrils for use as immunogen in mice. We obtained multiple monoclonal antibody (mAb) clones that were reactive against hIAPP protofibrils. A secondary screen was carried out to identify clones that cross-reacted with amyloid beta-peptide (Aβ42) protofibrils, but not with Aβ40 monomers. These mAbs were further characterized in several in vitro assays, in immunohistological studies of a mouse model of Alzheimer's disease (AD) and in AD patient brain tissue. We show that mAbs obtained by immunizing mice with the NUCB1-hIAPP complex cross-react with Aβ42, specifically targeting protofibrils and inhibiting their further aggregation. In line with conformation-specific binding, the mAbs appear to react with an intracellular antigen in diseased tissue, but not with amyloid plaques. We hypothesize that the mAbs we describe here recognize a secondary or quaternary structural epitope that is common to multiple amyloid protofibrils. In summary, we report a method to create mAbs that are conformation-sensitive and sequence-independent and can target more than one type of protofibril species.
Identifiants
pubmed: 30663210
doi: 10.1111/jcmm.14119
pmc: PMC6378190
doi:
Substances chimiques
Amyloid
0
Amyloid beta-Peptides
0
Antibodies, Monoclonal
0
Epitopes
0
Islet Amyloid Polypeptide
0
NUCB1 protein, human
0
Nucleobindins
0
Peptide Fragments
0
amyloid beta-protein (1-42)
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2103-2114Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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