Fluorescent Peptides Sequester Redox Copper to Mitigate Oxidative Stress, Amyloid Toxicity, and Neuroinflammation

Alzheimer's disease is a progressive neurodegenerative disorder that significantly contributes to dementia. The lack of effective therapeutic interventions presents a significant challenge to global health. We have developed a set of short peptides (PN_Gln) conjugated with a dual-functional fluorophoric amino acid (N_Gln). The lead peptide, P2N_Gln, displays a high affinity for Cu²⁺, maintaining the metal ion in a redox-inactive state. This mitigates the cytotoxicity generated by reactive oxygen species (ROS), which are produced by Cu²⁺ under the reductive conditions of Asc and Aβ₁₆ or Aβ₄₂. Furthermore, P2N_Gln inhibits both Cu-dependent and -independent fibrillation of Aβ₄₂, along with the subsequent toxicity induced by Aβ₄₂. In addition, P2N_Gln exhibits inhibitory effects on the production of lipopolysaccharide (LPS)-induced ROS and reactive nitrogen species (RNS) in microglial cells. In vitro and cellular studies indicate that P2N_Gln could significantly reduce Aβ-Cu²⁺-induced ROS production, amyloid toxicity, and neuroinflammation, offering an innovative strategy against Alzheimer's disease.