PDF(Pubmed)
Abstract：
The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-β oligomers (SAβOs) accumulate early, prior to amyloid plaque formation. SAβOs induce memory impairment and disrupt cognitive function independent of amyloid-β plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SAβO (E3) nanobody generated from an alpaca immunized with SAβO. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SAβOs and amyloid-β plaques. The E3 nanobody traverses across the blood-brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SAβO and amyloid-β plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SAβOs are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SAβO nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer\'s disease.
摘要：
经典的淀粉样蛋白级联假说假设淀粉样蛋白斑块的聚集和细胞内过度磷酸化Tau缠结的积累，一起,导致严重的神经元死亡.然而,新兴的研究表明，可溶性淀粉样β寡聚体（SAβOs）早期积累，在淀粉样蛋白斑块形成之前。SAβOs诱导记忆障碍和破坏认知功能，而不依赖于淀粉样蛋白-β斑块，甚至在没有斑块形成的情况下。这项工作描述了由SAβO免疫的羊驼产生的新型抗SAβO（E3）纳米抗体的开发和表征。使用5XFAD小鼠的体外测定和体内研究表明，荧光素（FAM）标记的E3纳米抗体识别SAβO和淀粉样蛋白β斑块。E3纳米抗体穿过血脑屏障，并与5XFAD小鼠大脑中的淀粉样蛋白结合。小鼠大脑成像显示，SAβO和淀粉样蛋白-β斑块不仅大小不同，形状,和形态学，而且在大脑中也有明显的空间分布。SAβOs与神经元相关，而淀粉样蛋白斑存在于细胞外基质中。这项研究的结果表明，SAβO纳米抗体可以作为诊断剂，在阿尔茨海默病中具有潜在的热不可知应用。
