Screening a specific Zn(II)-binding peptide for improving the cognitive decline of Alzheimer's disease in APP/PS1 transgenic mice by inhibiting Zn2+-mediated amyloid protein aggregation and neurotoxicity

摘要: Zn2+ has been implicated in the progression of Alzheimer's disease (AD), as amyloid-β protein (Aβ) aggregation and neurotoxicity are mediated by zinc ions. Therefore, development metal chelators for inhibiting regulating metal-triggered Aβ received attention a strategy treating AD. Here, we used an approach based on phage display to screen Zn(ii)-binding peptide that specifically blocks Zn-triggered aggregation. A fixed Zn(ii) resin was prepared using Ni-IDA affinity resin, target screened interaction with heptapeptide library. After negative biopanning against IDA four rounds positive Zn(ii), high specificity phages were obtained. Through DNA sequencing ELISA, 15 sets peptides histidine contents identified. We chose highly specific sequence H-M-Q-T-N-H-H, its abilities chelate inhibit Zn2+-mediated assessed vitro. loaded onto PEG-modified chitosan nanoparticles (NPs) improve stability bioavailability binding peptide. NPs (PEG/PZn-CS NPs) reduced concentrations secretion mouse neuroblastoma (N)2a cells stably over-expressing APP Swedish mutation (N2aswe). Zn2+-Induced neurotoxicity, oxidative stress, apoptosis attenuated PEG/PZn-CS NPs. Intranasal administration improved cognitive ability APPswe/PS1d9 (APP/PS1) double-transgenic mice plaques brain. This study indicated have promise potential anti-AD agent.