Real-Time Detection and Visualization of Amyloid-β Aggregates Induced by Hydrogen Peroxide in Cell and Mouse Models of Alzheimer's Disease

Oxidative stress, caused by an imbalance between the production and the accumulation of Reactive Oxygen Species (ROS), is a prominent cause of the neurotoxicity induced by aggregated Amyloid-β (Aβ) in Alzheimer's disease (AD). Tools that can directly detect and monitor the presence and amount of Aβ-induced ROS are still lacking. We report herein the first Aβ-targeted ratiometric H₂O₂-responsive fluorescent probe for real-time detection and monitoring of the Aβ-induced H₂O₂ level in cell and AD mouse models. The H₂O₂-responsive probe is constructed based on a methylamino-substituted quinolinium-based cyanine as the fluorescence moiety and a phenylboronate ester as the sensing reaction site. This sensing probe exhibits a large emission wavelength shift of ∼87 nm upon reacting with H₂O₂, a high binding selectivity for Aβ, and a faster response toward H₂O₂ in the presence of Aβ, concomitant with an enhanced fluorescence intensity, hence greatly boosting the sensitivity of in-situ H₂O₂ detection. This biocompatible and nontoxic probe is capable of ratiometrically detecting and imaging endogenous H₂O₂ induced by Aβ in a neuronal cell model. Remarkably, this Aβ-targeted H₂O₂-responsive probe is also able to detect, monitor, and differentiate different Aβ-induced H₂O₂ levels in real time in different age groups of transgenic AD mice in which the cerebral H₂O₂ level increases age dependently concomitant with the plaque contents. Therefore, this smart probe can act as a powerful tool to diagnose high-risk subjects and diseased brains of AD and to further study the role of ROS in AD pathology.

Alzheimer’s disease; Aβ-enhanced sensitivity; Aβ-targeting; H2O2-responsive fluorescent probe; in-vivo detection; ratiometric imaging.