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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

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Abstract

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 of metal chelators for inhibiting and regulating metal-triggered Aβ aggregation has received attention as a strategy for treating AD. Here, we used an approach based on phage display to screen for a Zn(II)-binding peptide that specifically blocks Zn-triggered Aβ aggregation. A fixed Zn(II) resin was prepared using Ni-IDA affinity resin, and the target Zn(II) was screened by interaction with a heptapeptide phage library. After negative biopanning against IDA and four rounds of positive biopanning against Zn(II), high specificity Zn(II)-binding phages were obtained. Through DNA sequencing and ELISA, 15 sets of Zn(II)-binding peptides with high histidine contents were identified. We chose a highly specific peptide against Zn(II) with the sequence of H-M-Q-T-N-H-H, and its abilities to chelate Zn2+ and inhibit Zn2+-mediated Aβ aggregation were assessed in vitro. We loaded the Zn(II)-binding peptide onto PEG-modified chitosan nanoparticles (NPs) to improve the stability and the bioavailability of the Zn(II) binding peptide. PEG-modified chitosan NPs loaded with Zn(II)-binding peptide (PEG/PZn-CS NPs) reduced Zn2+ concentrations and Aβ secretion in mouse neuroblastoma (N)2a cells stably over-expressing the APP Swedish mutation (N2aswe). Zn2+-Induced neurotoxicity, oxidative stress, and apoptosis were attenuated by PEG/PZn-CS NPs. Intranasal administration of PEG/PZn-CS NPs improved the cognitive ability of APPswe/PS1d9 (APP/PS1) double-transgenic mice and reduced Aβ plaques in the mouse brain. This study indicated that a Zn(II)-binding peptide and its NPs have promise as a potential anti-AD agent.

Graphical abstract: 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

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Publication details

The article was received on 28 Apr 2019, accepted on 27 Sep 2019 and first published on 03 Oct 2019


Article type: Paper
DOI: 10.1039/C9BM00676A
Biomater. Sci., 2019, Advance Article

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    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

    X. Zhang, M. Zhong, P. Zhao, X. Zhang, Y. Li, X. Wang, J. Sun, W. Lan, H. Sun, Z. Wang and H. Gao, Biomater. Sci., 2019, Advance Article , DOI: 10.1039/C9BM00676A

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