ACS Chem Neurosci. 2019 Jun 19;10(6):2647-2657. doi: 10.1021/acschemneuro.9b00199. Epub 2019 May 3.
Misfolded amyloid-β (Aβ) is the key biomarker of Alzheimer's disease (AD), and discoveries of fluorescence chemicals visualizing such Aβ aggregates in the brain have made major contributions in postmortem and antemortem diagnosis of the disorder. Insoluble senile plaques of Aβ in brain tissues are commonly stained with thioflavin and congo red dyes and observed through microscopy, while those in living patient brains are detected via radioisotope-labeled fluorescence chemicals for positron emission tomography. Clinical evidence strongly supports the view that plaques are well-associated with the onset but not with the progression of AD. Plaques could accumulate while cognitive functions of at-risk individuals are still intact, and thus, another biomarker is needed to monitor neurodegeneration. Soluble Aβ oligomers are considered to have strong correlation with neuronal loss and brain atrophy as they are the most neurotoxic forms of misfolded Aβ. However, oligomer-targeting probes encounter several major difficulties in development. There is a significant structural distinction between two Aβ species-plaques are β-sheet-rich while oligomers are unordered-and it is still difficult to isolate and stabilize the oligomeric forms of Aβ. Due to these challenges, soluble oligomer-detecting imaging probes are relatively rare compared to the plaque-targeting chemical probes. This Review describes biochemical and optical characteristics of up-to-date fluorescence chemicals targeting insoluble plaques and soluble oligomers of Aβ. We also highlight the contributions of Aβ fluorescence chemicals to the clinical diagnosis of AD and technical challenges in searching for enhanced imaging probes.
错误折叠的淀粉样蛋白-β（Aβ）是阿尔茨海默病（AD）的关键生物标志物，发现能够可视化大脑中此类 Aβ 聚集物的荧光化学物质，为该疾病的死后和生前诊断做出了重大贡献。脑组织中不溶性老年斑 Aβ 通常用硫黄素和刚果红染料染色，并通过显微镜观察，而活患者大脑中的 Aβ 则通过放射性同位素标记的荧光化学物质进行正电子发射断层扫描检测。临床证据强烈支持这样一种观点，即斑块与 AD 的发病密切相关，但与疾病的进展无关。斑块可以在高危个体的认知功能仍然完整的情况下积累，因此，需要另一种生物标志物来监测神经退行性变。可溶性 Aβ 寡聚体被认为与神经元丧失和脑萎缩密切相关，因为它们是错误折叠 Aβ 中最具神经毒性的形式。然而，寡聚体靶向探针在开发过程中遇到了几个重大困难。两种 Aβ 物种之间存在显著的结构差异——斑块富含β-折叠，而寡聚体则无序——而且仍然难以分离和稳定 Aβ 的寡聚形式。由于这些挑战，与斑块靶向化学探针相比，可溶性寡聚体检测成像探针相对较少。本综述描述了针对不溶性斑块和可溶性 Aβ 寡聚体的最新荧光化学物质的生化和光学特性。我们还强调了 Aβ 荧光化学物质对 AD 临床诊断的贡献以及在寻找增强型成像探针方面的技术挑战。
