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.
Institute of Life Sciences, Fuzhou University, Fuzhou, Fujian Province, P. R.China.
J Alzheimers Dis. 2021;79(4):1613-1629. doi: 10.3233/JAD-191266.
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.
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.
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.
阿尔茨海默病（AD）是老年人痴呆症的常见病因。tau 的过度磷酸化和聚集与 AD 的临床进展相关；因此，针对 tau 聚集的治疗方法可能具有用于抗 AD 药物开发的应用潜力。已经发现几种 tau 聚集抑制剂，包括小分子和抗体，可减少 tau 的聚集和相应的病理学。
筛选一种能够抑制 tau 聚集并改善其细胞毒性的单链可变片段（scFv）抗体。
方法/结果：我们使用磷酸化 tau（pTau）作为抗原，通过高通量噬菌体抗体库筛选获得了一种 scFv 抗体。生化分析表明，该 scFv 抗体（scFv T1）具有很强的抑制 pTau 聚集的能力，无论是在稀溶液中还是在大分子拥挤的条件下。scFv T1 还可以体外解聚预先形成的 pTau 聚集体。此外，发现 scFv T1 能够抑制细胞外 pTau 聚集体的细胞毒性，并在与 hTauR406W 突变体共表达时改善转染果蝇眼睛中的 tau 介导的毒性。
这种 scFv T1 抗体可能是一种针对 AD 的潜在新型治疗剂。我们的方法可用于开发针对神经退行性疾病的新型蛋白质聚集治疗策略。
