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) conjugated with a dual-functional fluorophoric amino acid (N). The lead peptide, P2N, displays a high affinity for Cu, maintaining the metal ion in a redox-inactive state. This mitigates the cytotoxicity generated by reactive oxygen species (ROS), which are produced by Cu under the reductive conditions of Asc and Aβ or Aβ. Furthermore, P2N inhibits both Cu-dependent and -independent fibrillation of Aβ, along with the subsequent toxicity induced by Aβ. In addition, P2N 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 could significantly reduce Aβ-Cu-induced ROS production, amyloid toxicity, and neuroinflammation, offering an innovative strategy against Alzheimer's disease.