Fu Yi-Xuan, Liu Shi-Yu, Guo Wu-Yingzheng, Mei Long-Can, Dai Yi-Jie, Peng Xuan-Jian, Yin Jun, Wang Da-Wei, Yang Guang-Fu
State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China.
Department of Laboratory Medicine, School of Medicine, Yangtze University, Jingzhou, 434023, PR China.
Biosens Bioelectron. 2025 Mar 1;271:117051. doi: 10.1016/j.bios.2024.117051. Epub 2024 Dec 10.
As the global population ages, the incidence and prevalence of Alzheimer's disease (AD) continues to rise, posing a serious threat to human health. Butyrylcholinesterase (BChE), which is overexpressed in the brains of patients with AD, is a potential drug target and biomarker. However, the molecular mechanism underlying BChE's role in the AD process remains unclear. Therefore, the development of tools for BChE detection can aid in the diagnosis of AD and deepen our understanding of BChE's contribution to disease progression. Motivated by a bioinspired strategy based on the natural substrate of BChE, we designed a BChE fluorescent probe (HCYO) with a novel recognition group for BChE detection to assist in the early diagnosis of AD. This probe can selectively detect endogenous BChE with an excellent detection limit of 28.9 ng/mL. Using HCYO, we successfully imaged four-week-old mice with an ultraearly AD model, the early diagnosis of the disease. Furthermore, using this HCYO probe, we confirmed that BChE influences the inflammation-induced upregulation the levels of phosphorylated tau and Trigger Receptor Expressed on Myeloid Cells 2, impacting AD progression. These findings provide a crucial theoretical basis for the development of BChE inhibitors for AD treatment.
随着全球人口老龄化，阿尔茨海默病（AD）的发病率和患病率持续上升，对人类健康构成严重威胁。丁酰胆碱酯酶（BChE）在AD患者大脑中过度表达，是一个潜在的药物靶点和生物标志物。然而，BChE在AD进程中发挥作用的分子机制仍不清楚。因此，开发BChE检测工具有助于AD的诊断，并加深我们对BChE在疾病进展中作用的理解。受基于BChE天然底物的生物启发策略的推动，我们设计了一种用于BChE检测的具有新型识别基团的BChE荧光探针（HCYO），以辅助AD的早期诊断。该探针能够选择性地检测内源性BChE，检测限低至28.9 ng/mL，性能优异。利用HCYO，我们成功地对四周龄的超早期AD模型小鼠进行了成像，实现了对该疾病的早期诊断。此外，使用这种HCYO探针，我们证实BChE会影响炎症诱导的磷酸化tau蛋白和髓样细胞表达的触发受体2水平上调，从而影响AD的进展。这些发现为开发用于AD治疗的BChE抑制剂提供了关键的理论依据。
