期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 79, 期 4, 页码 1613-1629出版社
IOS PRESS
DOI: 10.3233/JAD-191266
关键词
Aggregation; Alzheimer's disease; Drosophila; single-chain variable fragment antibody; tau; tauopathy; toxicity
资金
- National Natural Science Foundation of China [31071296]
- Province Min-River Scholar Grant [XRC-0947]
- Special Funds for Coconstruction Project of Beijing Municipal Commission of Education
A new potential therapeutic agent against AD, the scFv T1 antibody, was screened in this study. It showed strong ability to inhibit tau aggregation in dilute solutions and under conditions of macromolecular crowding, and could depolymerize preformed tau aggregates in vitro, indicating its potential for treating neurodegenerative diseases.
Background: Alzheimer's disease (AD) is a common cause of dementia among elderly people. Hyperphosphorylation and aggregation of tau correlates with the clinical progression of AD; therefore, therapies targeting the aggregation of tau may have potential applications for anti-AD drug development. Several inhibitors of tau aggregation, including small molecules and antibodies, have been found to decrease the aggregation of tau and the corresponding pathology. Objective: To screen one kind of single-chain variable fragment (scFv) antibody which could inhibit the aggregation of tau and ameliorate its cytotoxicity. Methods/Results: Using phosphorylated tau (pTau) as an antigen, we obtained a scFv antibody via the screening of a high-capacity phage antibody library. Biochemical analysis revealed that this scFv antibody (scFv T1) had a strong ability to inhibit pTau aggregation both in dilute solutions and under conditions of macromolecular crowding. ScFv T1 could also depolymerize preformed pTau aggregates in vitro. Furthermore, scFv T1 was found to be able to inhibit the cytotoxicity of extracellular pTau aggregates and ameliorate tau-mediated toxicity when coexpressed with a hTauR406W mutant in the eye of transgenic Drosophila flies. Conclusion: This scFv T1 antibody may be a potential new therapeutic agent against AD. Our methods can be used to develop novel strategies against protein aggregation for the treatment of neurodegenerative diseases.
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