共域化
荧光
化学
连接器
生物物理学
共轭体系
纤维
部分
τ蛋白
荧光寿命成像显微镜
立体化学
生物化学
分子生物学
阿尔茨海默病
生物
聚合物
病理
操作系统
物理
有机化学
计算机科学
医学
疾病
量子力学
作者
Kwang‐Su Park,Mi Kyoung Kim,Yujin Seo,Taewoong Ha,K. M. Yoo,Seung Jae Hyeon,Yu Jin Hwang,Jung‐Hee Lee,Hoon Ryu,Hyunah Choo,Youhoon Chong
标识
DOI:10.1021/acschemneuro.7b00224
摘要
Tau aggregation in neuronal cells has recently received significant attention as a robust predictor of the progression of Alzheimer’s disease (AD) because of its proven correlation with the degree of cognitive impairment in AD patients. Accordingly, noninvasive imaging of tau aggregates has been highlighted as a promising diagnostic tool for AD. We have previously identified a tau-specific “turn-on” near-infrared fluorescent (NIRF) probe (1), and, in this study, structural modification was performed to optimize its physicochemical as well as fluorescence properties. Thus, a series of fluorescent dyes (2a–2j) composed of a variously substituted difluoroboron β-diketonate and an N,N-dimethylaniline moiety linked by a length-extendable π-bridge were prepared. Among those, isobutyl-substituted difluoroboron β-ketonate with a π-conjugated 1,4-butadienyl linker (2e) showed the most promising properties as a tau-specific NIRF probe. Compared with 1, the “turn-on” fluorescence of 2e was more specific to tau fibrils, and it showed 8.8- and 6.2-times higher tau-over-Aβ and tau-over-BSA specificity, respectively. Also, the fluorescence intensity of 2e upon binding to tau fibrils was substantially higher (∼2.9 times) than that observed from 1. The mechanism for tau-specificity of 2e was investigated, which suggested that the molecular rotor-like property of 2e enables specific recognition of the microenvironment of tau aggregates to emit strong fluorescence. In transgenic cell lines stably expressing GFP-tagged tau proteins, 2e showed good colocalization with tau-GFP. Moreover, the fluorescence from 2e exhibited almost complete overlap with p-Tau antibody staining in the human AD brain tissue section. Collectively, these observations demonstrate the potential of 2e as a tau-specific fluorescent dye in both in vitro and ex vivo settings.
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