Abstract

Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder characterized by the buildup of peptides called amyloid-b (Ab) into plaques, metal ion imbalances, and oxidative stress. Together, these factors contribute to neuronal damage and cognitive decline. Oxidative stress occurs when reactive oxygen species (ROS)–unstable molecules that can damage cells–accumulate in the brain. In the brains of individuals with AD, high levels of metals like copper and zinc are found within Ab plaques. These metal ions interact with Ab, influencing its aggregation and toxicity. In particular, redox-active metal ions, such as Cu(I/II), can bind to Ab and catalyze the formation of ROS, thereby worsening oxidative stress and leading to neurotoxicity. Given the complex nature of AD, there is significant interest in developing therapeutic agents that target both metal-free and metal-bound Ab while also reducing ROS levels. Here, we present hydrogen peroxide (H₂O₂)-responsive, redox-inactive molecules, BE-1 and BE-2. These compounds are designed to enhance the chemical and biological properties of redox-active molecules and trigger their multiple reactivities under oxidative stress conditions. The BE molecules contain a boronic ester functional group that is chemically transformed into redox-active forms in the presence of H₂O₂. Once activated, the BE compounds initiate oxidative modifications of Ab peptides, forming covalent bonds that alter their aggregation and reduce cytotoxicity. Our findings indicate that this boron-masking strategy effectively activates redox-active compounds in a targeted manner, presenting a promising therapeutic approach to address the complex pathology of AD.