Kreutzer Adam G, Malonis Ryan J, Parrocha Chelsea Marie T, Tong Karen, Guaglianone Gretchen, Nguyen Jennifer T, Diab Michelle N, Lai Jonathan R, Nowick James S
Department of Chemistry, University of California Irvine, Irvine, CA 92697.
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461.
Pept Sci (Hoboken). 2024 Mar;116(2). doi: 10.1002/pep2.24333. Epub 2023 Sep 18.
Monoclonal antibodies (mAbs) that target the P-amyloid peptide (Aβ) are important Alzheimer's disease research tools and are now being used as Alzheimer's disease therapies. Conformation-specific mAbs that target oligomeric and fibrillar Aβ assemblies are of particular interest, as these assemblies are associated with Alzheimer's disease pathogenesis and progression. This paper reports the generation of rabbit mAbs against two different triangular trimers derived from Aβ. These antibodies are the first mAbs generated against Aβ oligomer mimics in which the high-resolution structures of the oligomers are known. We describe the isolation of the mAbs using single B-cell sorting of peripheral blood mononuclear cells (PBMCs) from immunized rabbits, the selectivity of the mAbs for the triangular trimers, the immunoreactivity of the mAbs with aggregated Aβ, and the immunoreactivity of the mAbs in brain tissue from the 5xFAD Alzheimer's disease mouse model. The characterization of these mAbs against structurally defined trimers derived from Aβ enhances understanding of antibody-amyloid recognition and may benefit the development of diagnostics and immunotherapies in Alzheimer's disease.
靶向β-淀粉样肽（Aβ）的单克隆抗体（mAb）是阿尔茨海默病重要的研究工具，目前正被用作阿尔茨海默病的治疗方法。靶向寡聚体和纤维状Aβ聚集体的构象特异性单克隆抗体尤其受关注，因为这些聚集体与阿尔茨海默病的发病机制和进展相关。本文报道了针对源自Aβ的两种不同三角形三聚体产生兔单克隆抗体。这些抗体是针对已知寡聚体高分辨率结构的Aβ寡聚体模拟物产生的首批单克隆抗体。我们描述了使用来自免疫兔的外周血单个核细胞（PBMC）的单B细胞分选来分离单克隆抗体，单克隆抗体对三角形三聚体的选择性，单克隆抗体与聚集Aβ的免疫反应性，以及单克隆抗体在5xFAD阿尔茨海默病小鼠模型脑组织中的免疫反应性。这些针对源自Aβ的结构明确的三聚体的单克隆抗体的表征增强了对抗体 - 淀粉样蛋白识别的理解，并可能有益于阿尔茨海默病诊断和免疫疗法的开发。
