Construction of a bifunctional near-infrared fluorescent probe for visualization of copper (II) ions and amyloid-β aggregates in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by multiple interconnected pathological factors, including the formation of amyloid-β (Aβ) plaques and the abnormal accumulation of copper (II) ions (Cu²⁺). The complex interplay between these factors has hindered the development of effective therapeutic agents. The accumulation of Cu²⁺ not only accelerates Aβ aggregation, but also generates reactive oxygen species through the Fenton reaction, leading to oxidative damage to neurons. While the interaction between Cu²⁺ and Aβ₄₂ aggregates has been investigated, there is inadequate research into fluorescent probes capable of detecting both Cu²⁺ and Aβ₄₂ aggregates. This study presents a novel bifunctional near-infrared (NIR) fluorescent probe, LDMD-N, designed using a “Cu²⁺ activation” strategy. LDMD-N exhibited excellent performance for rapid detection (5 min) and high sensitivity (LOD = 0.0543 µM) of Cu²⁺ in vitro, and enabled visual fluorescence imaging of fluctuating Cu²⁺ levels in living cells. Notably, we observed that Cu²⁺ promoted Aβ₄₂ aggregation in zebrafish using this probe. In vivo and in vitro staining experiments demonstrated that LDMD-N could effectively distinguish AD model mice from wild-type (Wt) mice. This Cu²⁺ activated bifunctional NIR fluorescent probe provides a promising tool for elucidating the intricate relationship between Aβ₄₂ aggregates and Cu²⁺. This approach may contribute to a deeper understanding of AD mechanisms and aid in the development of targeted therapeutic strategies.