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 Cu 2+ , maintaining the metal ion in a redox-inactive state. This mitigates the cytotoxicity generated by reactive oxygen species (ROS), which are produced by Cu 2+ under the reductive conditions of Asc and Aβ 16 or Aβ 42 . Furthermore, P2N Gln inhibits both Cu-dependent and -independent fibrillation of Aβ 42 , along with the subsequent toxicity induced by Aβ 42 . 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-Cu 2+ -induced ROS production, amyloid toxicity, and neuroinflammation, offering an innovative strategy against Alzheimer's disease.