Peroxynitrite and amyloid-β dual-activated near-infrared theranostic probe for oxidative stress monitoring in Alzheimer's disease

Abstract

Amyloid-β (Aβ), the hallmark of Alzheimer's disease (AD), is known to induce reactive oxygen species, peroxynitrite (ONOO⁻) which plays a crucial role in the pathogenesis and progression of this incurable disease. However, the development of tools that can directly detect the presence and monitor the level of Aβ-induced ONOO⁻ remains a great challenge. We report herein the development of an Aβ and ONOO⁻ synergistically activated NIR fluorescent probe for highly selective imaging of Aβ-induced ONOO⁻ level in vivo. Importantly, this responsive probe exhibits not only synergistically strong enhancement of fluorescence at 655 nm upon reacting with ONOO⁻ in the presence of Aβ but also high sensitivity down to 13 nM with minimal interference. The strong Aβ binding and low cytotoxicity enable the probe to successfully apply for detecting and visualizing endogenous ONOO⁻ level induced by Aβ in AD cell model. Remarkably, this ONOO⁻-responsive probe can be applied effectively to detect, monitor, and distinguish varying ONOO⁻ levels induced by Aβ in different age groups of AD mice, in which cerebral ONOO⁻ level rises with increasing age of AD mice along with Aβ plaque accumulation. Furthermore, the potent neuroprotection against Aβ-induced toxicity and anti-Aβ aggregation effect of the ONOO⁻-reaction product of the probe offer an extra therapeutic advantage of this ONOO⁻-responsive probe. In essence, this multifunctional theranostic probe can serve as a highly sensitive and specific imaging tool for visualizing and monitoring of ONOO⁻ level in the presence of Aβ in vivo, thereby facilitating more accurate early diagnosis and therapy of AD.