Rational Design of in Vivo Tau Tangle-Selective Near-Infrared Fluorophores: Expanding the BODIPY Universe

Abstract

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 (VQIVYK) 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.

Dual-functional protein for one-step production of a soluble and targeted fluorescent dye

“…Up to now, tremendous efforts have been made to overcome the drawbacks mentioned above of NIR fluorescent probes, but in two separate steps 15 - 18 . In the first step, numerous polar groups like sulfonate, glycol, and carboxylate are linked to the core structures of NIR dyes to gain solubility in aqueous solutions 19 , 20 .…”

Nitrogen‐Doped Carbonized Polymer Dots: A Potent Scavenger and Detector Targeting Alzheimer's β‐Amyloid Plaques

“…The non-covalent interactions could cause a rigid entanglement, limiting the molecular vibration and rotation, and thereby facilitating the red emission. [37,[75][76][77] To further clarify the potential of CPDs as a theranostic agent for remodeling and monitoring Aβ 40 fibrils, the fluorescence kinetics of CPDs was recorded and analyzed during the co-incubation with Aβ 40 fibrils. As illustrated in Figure 5b, at low CPDs concentrations (1-10 µg mL −1 ), CPDs intensity gradually increased to a platform and remained stable for a while till starting decrease (which can be seen at 10 µg mL −1 ).…”

Nucleic Acid Aptamers: Emerging Applications in Medical Imaging, Nanotechnology, Neurosciences, and Drug Delivery

“…In AD, the combined accumulation and deposition of abnormal forms of tau protein and amyloid β (Aβ) peptides in the human brain is followed by a progressive functional disruption of neuronal networks [ 114 ]. Consequently, both tau and Aβ proteins represent valid targets for aptamer selection experiments.…”