Amphiphilic Tetraphenylethylene Derivative with Hydrophobic–Hydrophilic Complementarity to Amyloid Oligomers for <i>in Situ</i> Imaging and Modulation of Membrane-Disruptive Neurotoxicity

Amyloid oligomers are key targets for probing and regulating neuronal activities and disorder, whose recognition and detection, however, remain challenging due to their transient and heterogeneous nature. In this work, inspired by the membrane interactive and disruptive behavior of oligomers, we report the molecular tailoring of an activatable fluorescent probe (TPO) that selectively recognizes amyloid-β (Aβ) oligomers and enables real-time visualization of amyloid aggregation and dynamics. The integration of a tetraphenylethylene core, a dicyanovinyl electron-accepting unit, and phosphate groups collectively confers high affinity and specificity for β-hairpin-rich oligomeric surfaces, for which the recognition mechanism was further explored with structural analogues and molecular simulation. Capable of discriminating against monomers and fibrils, TPO provides rapid and sensitive turn-on fluorescence for monitoring early Aβ fibrillogenesis and subcellular imaging of oligomers in living neuronal cells. Notably, by occupying key hydrophobic patches and charged residues that mediate oligomer-membrane interactions, TPO suppresses Aβ oligomer-induced neurotoxicity. These findings establish TPO as a dual-function molecular probe for tracking early amyloid assemblies and modulating oligomer-driven neuronal damage, offering new opportunities for mechanistic investigation and therapeutic development in neurodegenerative diseases.