Amyloid‑β guided responsive theranostic fluorescent probe for imaging of endogenous hydrogen peroxide in Alzheimer disease

Alzheimer disease (AD) is an irreversible and incurable neurodegenerative disorder. Amyloid-β (Aβ), the pathological hallmarks of AD, is known to induce oxidative stress due to the overproduction of reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂) leading to neurotoxicity and ultimately, neuronal death. Therefore, H₂O₂ could be a reliable biomarker for more precise detection and diagnosis of AD. Herein, we report the development of highly sensitive and effective ratiometric Aβ-guided H₂O₂-responsive theranostic probes for sensing and tracking of endogenous H₂O₂ in AD mouse models. Among the probes synthesized, HY3 was shown to possess superior multifunctional properties including low cytotoxicity and good biocompatibility, strong binding with Aβ and large Aβ binding-induced fluorescence enhancement, excellent H₂O₂ specificity, superior stability, and of particular importance, rapid response, and high sensitivity toward H₂O₂ in the presence of Aβ for selective imaging and monitoring of endogenous H₂O₂ in real time in AD mouse model. Molecular docking revealed the difference in the binding motif and interactions of the probe HY3 and its H₂O₂-oxidized product, HY2 with Aβ fibrils giving rise to the difference of Aβ binding-induced fluorescence enhancement between them. Impressively, with the promotion of Aβ, HY3 was able to detect the endogenous H₂O₂ level ratiometrically in AD cell model and differentiate the difference between the normal and AD cells. More importantly, the excellent BBB permeable and biocompatible HY3 probe enabled it to target the senile plaques and serve as an effective and highly sensitive ratiometric fluorescent probe to image and monitor endogenous H₂O₂ level in vivo in different age groups of AD mice. Furthermore, the inhibitory function against Aβ aggregation of HY2 offers an additional benefit for the therapeutic use of this versatile probe. Our results suggested that H₂O₂ could be a useful and reliable biomarker for AD and HY3 is a highly promising and effective tool in the detection of Aβ-induced H₂O₂ level in vivo for more precise diagnosis of AD as well as can serve as a potential pro-drug to treat AD.