Visual Whole-Process Monitoring Dynamic Phase Separation of Autophagic Lysosomes in Alzheimer’s Disease by a Lysosome-Targeted pH-Activated Fluorescence Probe

Although liquid-liquid phase separation (LLPS) of amyloid-β (Aβ) aggregates is a critical driver of Alzheimer's disease (AD) progression, the role of lysosomal acidification defects remains poorly understood during this process. Herein, we successfully develop a synthetic strategy involving the construction of pH-activated probe backbones by the atom transfer radical polymerization technique with methacrylates with different substituents as monomers. Subsequently, a fluorescence probe is prepared by integrating hydrophobic aggregation-induced luminescence (AIE) fluorescence dyes and aggregation-induced bursting (ACQ) dyes into ACQ/AIE ratio imaging nanoparticles through covalent bonding and self-assembly techniques. Such AIE probe can monitor lysosomal acidification defects in AD and elucidate their role in Aβ phase separation. Interestingly, our new findings reveal that Aβ accumulation synergizes with lysosomal dysfunction (the pH value itself has not changed) to induce pathological LLPS, thereby providing a novel approach for phase modulation and attenuating AD progression. Taken together, our design concept provides a novel strategy to regulate phase separation, potentially reducing or delaying Aβ aggregation and AD progression.