The elucidation of the cause of Alzheimer’s disease remains one of the greatest questions in neurodegenerative research. The lack of highly reliable low-cost sensors to study the structural changes in key proteins during the progression of the disease is a contributing factor to this lack of insight. In the current work, we describe the rational design and synthesis of two fluorescent BODIPY-based probes, named Tau 1 and Tau 2. The probes were evaluated on the molecular surface formed by a fibril of the PHF6 (³⁰⁶VQIVYK³¹¹) tau fragment using molecular docking studies to provide a potential molecular model to rationalize the selectivity of the new probes as compared to a homologous Aβ-selective probe. The probes were synthesized in a few steps from commercially available starting products and could thus prove to be highly cost-effective. We demonstrated the excellent photophysical properties of the dyes, such as a large Stokes shift and emission in the near-infrared window of the electromagnetic spectrum. The probes demonstrated a high selectivity for self-assembled microtubule-associated protein tau (Tau protein), in both solution and cell-based experiments. Moreover, the administration to an acute murine model of tauopathy clearly revealed the staining of self-assembled hyperphosphorylated tau protein in pathologically relevant hippocampal brain regions. Tau 1 demonstrated efficient blood–brain barrier penetrability and demonstrated a clear selectivity for tau tangles over Aβ plaques, as well as the capacity for in vivo imaging in a transgenic mouse model. The current work could open up avenues for the cost-effective monitoring of the tau protein aggregation state in animal models as well as tissue staining. Furthermore, these fluorophores could serve as the basis for the development of clinically relevant sensors, for example based on PET imaging.

中文翻译：

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体内牛头缠结选择性近红外荧光团的合理设计：扩展BODIPY宇宙

阐明阿尔茨海默氏病的原因仍然是神经退行性研究中的最大问题之一。缺乏高度可靠的低成本传感器来研究疾病进展过程中关键蛋白质的结构变化，是导致缺乏洞察力的一个因素。在当前的工作中，我们描述了两个荧光的基于BODIPY的探针Tau 1和Tau 2的合理设计和合成。该探针是在由PHF6（³⁰⁶ VQIVYK ^311）的原纤维形成的分子表面上进行评估的。）tau片段，通过分子对接研究提供了一个潜在的分子模型，与同源Aβ-选择性探针相比，可以合理化新探针的选择性。探针是由市售起始产品分几步合成的，因此可以证明具有很高的成本效益。我们展示了染料的出色光物理特性，例如电磁光谱的近红外窗口中的大斯托克斯位移和发射。探针在溶液实验和基于细胞的实验中均显示出对自组装微管相关蛋白tau（Tau蛋白）的高选择性。此外，对牛头病的急性鼠模型的施用清楚地揭示了在病理相关的海马脑区域中自组装的超磷酸化的tau蛋白的染色。转基因小鼠模型中的体内成像。当前的工作可以为以低成本方式监测动物模型中tau蛋白聚集状态以及组织染色开辟途径。此外，这些荧光团可以用作开发临床相关传感器的基础，例如基于PET成像的传感器。