A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aβ Aggregation

Copper (Cu) has been implicated in the progression of Alzheimer’s disease (AD), and aggregation of Cu and amyloid β peptide (Aβ) are considered key pathological features of AD. Metal chelators are considered to be potential therapeutic agents for AD because of their capacity to reduce metal ion-indu...

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Published in:International journal of molecular sciences 2021-06, Vol.22 (13), p.6842
Main Authors: Zhang, Xiaoyu, Zhang, Xiancheng, Zhong, Manli, Zhao, Pu, Guo, Chuang, Li, You, Xu, He, Wang, Tao, Gao, Huiling
Format: Article
Language:English
Subjects:
Alzheimer's disease
Amino acids
Binding
Binding sites
Brain
Cell culture
Chelating agents
Chemical compounds
Cloning
Copper
Cu(II)
Display devices
Homeostasis
Ion distribution
Metal ions
metal-binding peptide
Metals
Neurotoxicity
Pathogenesis
Peptides
Phage display
Phages
Pharmacology
Proteins
Toxicity
Zinc
β-Amyloid
β-Site APP-cleaving enzyme 1
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Summary:Copper (Cu) has been implicated in the progression of Alzheimer’s disease (AD), and aggregation of Cu and amyloid β peptide (Aβ) are considered key pathological features of AD. Metal chelators are considered to be potential therapeutic agents for AD because of their capacity to reduce metal ion-induced Aβ aggregation through the regulation of metal ion distribution. Here, we used phage display technology to screen, synthesize, and evaluate a novel Cu(II)-binding peptide that specifically blocked Cu-triggered Aβ aggregation. The Cu(II)-binding peptide (S-A-Q-I-A-P-H, PCu) identified from the phage display heptapeptide library was used to explore the mechanism of PCu inhibition of Cu2+-mediated Aβ aggregation and Aβ production. In vitro experiments revealed that PCu directly inhibited Cu2+-mediated Aβ aggregation and regulated copper levels to reduce biological toxicity. Furthermore, PCu reduced the production of Aβ by inhibiting Cu2+-induced BACE1 expression and improving Cu(II)-mediated cell oxidative damage. Cell culture experiments further demonstrated that PCu had relatively low toxicity. This Cu(II)-binding peptide that we have identified using phage display technology provides a potential therapeutic approach to prevent or treat AD.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22136842