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

ABSTRACT

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 (PNGln) conjugated with a dual-functional fluorophoric amino acid (NGln). The lead peptide, P2NGln, 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 Aß16 or Aß42. Furthermore, P2NGln inhibits both Cu-dependent and -independent fibrillation of Aß42, along with the subsequent toxicity induced by Aß42. In addition, P2NGln 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 P2NGln could significantly reduce Aß-Cu2+-induced ROS production, amyloid toxicity, and neuroinflammation, offering an innovative strategy against Alzheimer's disease.