Dual Efficacy of a Catalytic Anti-Oligomeric Aβ42 scFv Antibody in Clearing Aβ42 Aggregates and Reducing Aβ Burden in the Brains of Alzheimer's Disease Mice.
Alzheimer’s disease (AD)
Amyloid β-protein (Aβ)
Catalytic antibody
Degradation
Single-chain variable fragment (scFv)
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
received:
03
04
2023
accepted:
25
05
2023
medline:
4
9
2023
pubmed:
16
6
2023
entrez:
16
6
2023
Statut:
ppublish
Résumé
One of the primary pathological mechanisms underlying Alzheimer's disease (AD) is the deposition of amyloid β-protein (Aβ42) aggregates in the brain. In this study, a catalytic anti-oligomeric Aβ42 scFv antibody, HS72, was identified by screening a human antibody library, its ability to degrade Aβ42 aggregates was defined, and its role in the reduction of Aβ burden in the AD mouse brain was evaluated. HS72 specifically targeted Aβ42 aggregates with an approximately 14-68 kDa range. Based on molecular docking simulations, HS72 likely catalyzed the hydrolytic cleavage of the His13-His14 bond of Aβ42 chains in an Aβ42 aggregate unit, releasing N/C-terminal fragments and Aβ42 monomers. Degradation of Aβ42 aggregates by HS72 triggered a considerable disassembly or breakdown of the Aβ42 aggregates and greatly reduced their neurotoxicity. Aβ deposit/plaque load in the hippocampus of AD mice was reduced by approximately 27% after 7 days (once daily) of intravenous HS72 administration, while brain neural cells were greatly restored and their morphology was drastically improved. The above efficacies of HS72 were all greater than those of HT7, a simple anti-oligomeric Aβ42 scFv antibody. Although a catalytic anti-oligomeric Aβ42 antibody may have a slightly lower affinity for Aβ42 aggregates than a simple anti-oligomeric Aβ42 antibody, the former may display a stronger overall efficacy (dual efficacy of induction and catalysis) than the latter (induction alone) in clearing Aβ42 aggregates and improving histopathological changes in AD brain. Our findings on the catalytic antibody HS72 indicate the possibility of functional evolution of anti-oligomeric Aβ42 antibodies and provide novel insights into the immunotherapy of AD.
Identifiants
pubmed: 37326904
doi: 10.1007/s12035-023-03406-8
pii: 10.1007/s12035-023-03406-8
doi:
Substances chimiques
amyloid beta-protein (1-42)
0
Amyloid beta-Peptides
0
Antibodies, Catalytic
0
Peptide Fragments
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5515-5532Subventions
Organisme : National Natural Science Foundation of China
ID : 31970883
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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