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 (A β ), the pathological hallmarks of AD, is known to induce oxidative stress due to the overproduction of reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) leading to neurotoxicity and ultimately, neuronal death. Therefore, H 2 O 2 could be a reliable biomarker for more precise detection and diagnosis of AD. Herein, we report the development of highly sensitive and effective ratiometric A β -guided H 2 O 2 -responsive theranostic probes for sensing and tracking of endogenous H 2 O 2 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 A β and large A β binding-induced fluorescence enhancement, excellent H 2 O 2 specificity, superior stability, and of particular importance, rapid response, and high sensitivity toward H 2 O 2 in the presence of A β for selective imaging and monitoring of endogenous H 2 O 2 in real time in AD mouse model. Molecular docking revealed the difference in the binding motif and interactions of the probe HY3 and its H 2 O 2 -oxidized product, HY2 with A β fibrils giving rise to the difference of A β binding-induced fluorescence enhancement between them. Impressively, with the promotion of A β, HY3 was able to detect the endogenous H 2 O 2 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 H 2 O 2 level in vivo in different age groups of AD mice. Furthermore, the inhibitory function against A β aggregation of HY2 offers an additional benefit for the therapeutic use of this versatile probe. Our results suggested that H 2 O 2 could be a useful and reliable biomarker for AD and HY3 is a highly promising and effective tool in the detection of A β -induced H 2 O 2 level in vivo for more precise diagnosis of AD as well as can serve as a potential pro-drug to treat AD.