Novel Benzothiazole Derivatives as Fluorescent Probes for Detection of β-Amyloid and α-Synuclein Aggregates
Novel Benzothiazole Derivatives as Fluorescent Probes for Detection of β-Amyloid and α-Synuclein Aggregates
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DOI：
10.1021/acschemneuro.6b00450
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发表时间：
2017-08-01
影响因子：
5
通讯作者：
Saji, Hideo
中科院分区：
文献类型：
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作者：
Watanabe, Hiroyuki;Ono, Masahiro;Saji, Hideo
β-淀粉样蛋白（A β）和α-突触核蛋白（α-syn）的沉积分别是阿尔茨海默病（AD）和帕金森病（PD）的标志。用荧光探针检测这些蛋白质聚集体对于使用荧光显微镜在人脑组织上进行的临床前研究特别感兴趣。在这项研究中，我们新设计并合成了三个推挽式苯并噻唑（PP-BTA）衍生物作为荧光探针检测A β和α-syn聚集体。所有PP-BTA衍生物的荧光强度在与溶液中的A β（1-42）和α-syn聚集体结合后显著增加。在体外饱和结合试验中，PP-BTA衍生物表现出对A β（1-42）（Kd = 40-148 nM）和α-syn（Kd = 48-353 nM）聚集体的亲和力。特别地，PP-BTA-4清楚地染色了AD脑切片中由A β聚集体组成的老年斑。此外，它还标记了PD脑切片中由α-syn聚集体组成的Lewy小体。这些结果表明，PP-BTA-4可以作为一个有前途的荧光探针检测A β和α-syn聚集体。
Deposits of beta-amyloid (A beta) and alpha-synuclein (alpha-syn) are the hallmark of Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. The detection of these protein aggregates with fluorescent probes is particularly of interest for preclinical studies using fluorescence microscopy on human brain tissue. In this study, we newly designed and synthesized three push pull benzothiazole (PP-BTA) derivatives as fluorescent probes for detection of A beta and alpha-syn aggregates. Fluorescence intensity of all PP-BTA derivatives significantly increased upon binding to A beta(1-42) and alpha-syn aggregates in solution. In in vitro saturation binding assays, PP-BTA derivatives demonstrated affinity for both A beta(1-42) (K-d = 40-148 nM) and alpha-syn (K-d = 48-353 nM) aggregates. In particular, PP-BTA-4 clearly stained senile plaques composed of A beta aggregates in the AD brain section. Moreover, it also labeled Lewy bodies composed of alpha-syn aggregates in the PD brain section. These results suggest that PP-BTA-4 may serve as a promising fluorescent probe for the detection of A beta and alpha-syn aggregates.