<br>针对 Aβ 寡聚体模拟物产生的抗体可识别阿尔茨海默病和相关淀粉样蛋白病脑组织中的病理特征,ACS Central Science

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针对 Aβ 寡聚体模拟物产生的抗体可识别阿尔茨海默病和相关淀粉样蛋白病脑组织中的病理特征
ACS Central Science ( IF 12.7 ) Pub Date : 2023-12-21 , DOI: 10.1021/acscentsci.3c00592
Adam G Kreutzer ₁ , Chelsea Marie T Parrocha ₂ , Sepehr Haerianardakani ₁ , Gretchen Guaglianone ₁ , Jennifer T Nguyen ₂ , Michelle N Diab ₁ , William Yong ₃ , Mari Perez-Rosendahl ₃ , Elizabeth Head ₃ , James S Nowick _{1,

2}

Affiliation

靶向 β-淀粉样蛋白肽（Aβ）及其相关组装体的抗体是阿尔茨海默病研究的重要工具，并已成为有前途的阿尔茨海默病疗法。本文报道了由 Aβ_17-36 β发夹组成的三角形 Aβ 三聚体模拟物的创建和表征，以及针对 Aβ 三聚体模拟物产生的多克隆抗体的产生和研究。Aβ 三聚体模拟物通过三角形三聚体角落的三个二硫键共价稳定，以产生均相低聚体。结构、生物物理和基于细胞的研究表明，Aβ 三聚体模拟物与全长 Aβ 的寡聚体具有共同的特征。X 射线晶体学阐明了三聚体的结构，并揭示了三聚体的四个拷贝聚集在一起形成十二聚体。SDS-PAGE、尺寸排阻色谱和动态光散射表明，三聚体也在溶液中形成高阶组装体。基于细胞的毒性测定显示，三聚体会引发 LDH 释放，降低 ATP 水平，并激活 caspase-3/7 介导的细胞凋亡。对阿尔茨海默病患者和唐氏综合症患者的脑切片进行免疫染色研究表明，针对 Aβ 三聚体模拟物产生的多克隆抗体可识别病理特征，包括不同类型的 Aβ 斑块和脑淀粉样血管病。

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Antibodies Raised Against an Aβ Oligomer Mimic Recognize Pathological Features in Alzheimer’s Disease and Associated Amyloid-Disease Brain Tissue

Antibodies that target the β-amyloid peptide (Aβ) and its associated assemblies are important tools in Alzheimer’s disease research and have emerged as promising Alzheimer’s disease therapies. This paper reports the creation and characterization of a triangular Aβ trimer mimic composed of Aβ_17–36 β-hairpins and the generation and study of polyclonal antibodies raised against the Aβ trimer mimic. The Aβ trimer mimic is covalently stabilized by three disulfide bonds at the corners of the triangular trimer to create a homogeneous oligomer. Structural, biophysical, and cell-based studies demonstrate that the Aβ trimer mimic shares characteristics with oligomers of full-length Aβ. X-ray crystallography elucidates the structure of the trimer and reveals that four copies of the trimer assemble to form a dodecamer. SDS-PAGE, size exclusion chromatography, and dynamic light scattering reveal that the trimer also forms higher-order assemblies in solution. Cell-based toxicity assays show that the trimer elicits LDH release, decreases ATP levels, and activates caspase-3/7 mediated apoptosis. Immunostaining studies on brain slices from people who lived with Alzheimer’s disease and people who lived with Down syndrome reveal that the polyclonal antibodies raised against the Aβ trimer mimic recognize pathological features including different types of Aβ plaques and cerebral amyloid angiopathy.

更新日期：2023-12-21

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