A Single-Chain Variable Fragment Antibody Inhibits Aggregation of Phosphorylated Tau and Ameliorates Tau Toxicity in vitro and in vivo

Article type: Research Article

Authors: Li, Sen^{a; *} | Yi, Yushan^b | Cui, Ke^a | Zhang, Yanqiu^a | Chen, Yange^a | Han, Dou^a | Sun, Ling^b | Zhang, Xiaohui^b | Chen, Fei^b | Zhang, Yixin^c | Yang, Yufeng^{b; *}

Affiliations: [a] Department of Biochemistry and Molecular Biology, College of Life Sciences, Beijing Normal University, Gene engineering and Biotechnology Beijing Key Laboratory, National Demonstration Center for Experimental Life Sciences & Biotechnology Education, Beijing, P. R. China | [b] Institute of Life Sciences, Fuzhou University, Fuzhou, Fujian Province, P. R.China | [c] B CUBE Center for Molecular Bioengineering, Technische Universität Dresden, Dresden, Germany

Correspondence: [*] Correspondence to: Sen Li, Department of Biochemistry and Molecular Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, P. R. China. E-mail: [email protected]. and Yufeng Yang, Institute of Life Sciences, Fuzhou University, Fuzhou, Fujian Province, 350108, P. R. China. E-mail: [email protected].

Abstract: 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.

Keywords: Aggregation, Alzheimer’s disease, Drosophila , single-chain variable fragment antibody, tau, tauopathy, toxicity

DOI: 10.3233/JAD-191266

Journal: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1613-1629, 2021