N,N-Dimethylaminonaphthyl-modified dicyanoisophorone near-infrared probe for dual-functional imaging of β-amyloid aggregates and lipid droplets

Abstract

Dicyanoisophorone (DCIP)-based compounds, used as fluorescent probes of β-amyloid (Aβ) aggregates, exhibit limitations including a short emission wavelength and insufficient selectivity. To address these issues, we replaced the N,N-dimethylaminobenzene moiety with an N,N-dimethylaminonaphthalene group, leading to the development of a novel derivative, A13. This structural modification not only extends the π-conjugated system, thereby achieving a significantly red-shifted emission, but also improves the binding specificity of the probe for Aβ aggregates. The fluorescence intensity of A13 exhibited a remarkable 35-fold increase upon binding with Aβ aggregates, demonstrating superior performance compared to DCIP (13-fold) and indicating a strong binding affinity, with a dissociation constant (K_d) of 141.5 ± 15.2 nM. Molecular docking simulations were also performed to elucidate the binding mode between A13 and Aβ aggregates. Furthermore, owing to its enhanced lipophilicity, A13 could specifically label intracellular lipid droplets (LDs) and, more importantly, was able to detect real-time visualization of the complete cellular trafficking pathway of FITC-labeled Aβ monomers, including their cellular uptake and subsequent lysosomal delivery mediated by LDs. In vivo experiments showed that A13 effectively crossed the blood–brain barrier in mice, enabling near-infrared imaging of brain tissue. Notably, A13 exhibited distinct fluorescence patterns between wild-type mice and APP/PS1 transgenic models, successfully differentiating their cerebral fluorescence signals. These findings demonstrate that A13 can serve as a dual-functional fluorescent probe capable of detecting both Aβ aggregates and LDs, thus providing a novel tool for early diagnosis and pathological investigation of Alzheimer's disease.