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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

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Abstract

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.

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Abbreviations

AD:

Alzheimer’s disease

Aβ42:

Amyloid β-protein 1–42

scFv:

Single-chain variable fragment

HSA:

Human Serum Albumin

DMEM:

Dulbecco’s modified eagle’s medium

HPLC:

High-performance liquid chromatography

ELISA:

Enzyme-linked immunosorbent assay

SD:

Standard deviation

HE:

Hematoxylin-eosin

IHC:

Immunohistochemistry

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Acknowledgements

Authors thank Yanru Zheng of the School of Life Sciences, Jilin University for her technical assistance with section analysis.

Funding

This work was supported by a grant from the National Natural Science Foundation of China (No. 31970883).

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Authors and Affiliations

  1. Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, 130012, China

    Chuli Song, He Li, Changxin Zheng, Tianyu Zhang & Yingjiu Zhang

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  1. Chuli Song
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  2. He Li
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  3. Changxin Zheng
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  4. Tianyu Zhang
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Chuli Song, He Li, Tianyu Zhang, Changxin Zheng, Yingjiu Zhang. The first draft of the manuscript was written by Chuli Song and Yingjiu Zhang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yingjiu Zhang.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Servicebio Animal Welfare, Wuhan, China (approval number: 2022113).

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Song, C., Li, H., Zheng, C. et al. 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. Mol Neurobiol 60, 5515–5532 (2023). https://doi.org/10.1007/s12035-023-03406-8

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