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 (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.