Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
ACS Chem Neurosci. 2017 Aug 16;8(8):1656-1662. doi: 10.1021/acschemneuro.6b00450. Epub 2017 May 3.
Deposits of β-amyloid (Aβ) and α-synuclein (α-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 Aβ and α-syn aggregates. Fluorescence intensity of all PP-BTA derivatives significantly increased upon binding to Aβ(1-42) and α-syn aggregates in solution. In in vitro saturation binding assays, PP-BTA derivatives demonstrated affinity for both Aβ(1-42) (K = 40-148 nM) and α-syn (K = 48-353 nM) aggregates. In particular, PP-BTA-4 clearly stained senile plaques composed of Aβ aggregates in the AD brain section. Moreover, it also labeled Lewy bodies composed of α-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 Aβ and α-syn aggregates.
β-淀粉样蛋白（Aβ）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。使用荧光显微镜在人脑组织上进行临床前研究时，用荧光探针检测这些蛋白质聚集体尤其具有意义。在这项研究中，我们新设计并合成了三个推挽苯并噻唑（PP-BTA）衍生物作为用于检测 Aβ 和 α-syn 聚集体的荧光探针。所有 PP-BTA 衍生物与溶液中的 Aβ（1-42）和 α-syn 聚集体结合后，荧光强度均显著增加。在体外饱和结合测定中，PP-BTA 衍生物对 Aβ（1-42）（K = 40-148 nM）和 α-syn（K = 48-353 nM）聚集体均表现出亲和力。特别是，PP-BTA-4 可清晰染色 AD 脑切片中由 Aβ 聚集体组成的老年斑，并且还可以标记 PD 脑切片中由 α-syn 聚集体组成的路易体。这些结果表明，PP-BTA-4 可能是一种有前途的用于检测 Aβ 和 α-syn 聚集体的荧光探针。
