Abstract
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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by irreversible and progressive cognitive dysfunction and causes substantial medical and socioeconomic burden worldwide
We provided a general pipeline for the development of metal chelating agents by binding the target metal ion with peptides based on a phage library [33]
ICP-MSthat showed was a significant in intracellular copper after the addition of extra copper, and PCu treatment decreased the intracellular level of content after the addition of extra copper, and PCu treatment decreased the intracellular copper in cells (Figure 5C). These results indicate that PCu could inhibit the level of copper in cells (Figure 5C). These results indicate that PCu could production of amyloid-β peptide (Aβ) in N2a-sw by binding copper
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by irreversible and progressive cognitive dysfunction and causes substantial medical and socioeconomic burden worldwide. AD has been hypothesized to be a protein misfolding disease caused by the accumulation of misfolded amyloid-β peptide (Aβ) and tau protein, which are the major pathological hallmarks of AD [1,2]. Aβ is produced by the sequential cleavage of β-amyloid precursor protein (APP) by two enzymes, β-secretase and γ-secretase [3]. Aβ readily self-assembles into a variety of aggregates called oligomers, fibrils, and mature amyloid fibers. Aβ1-40 and Aβ1-42 are the two most abundant forms of. The level of Aβ1-40 is approximately 10 times higher than that of Aβ1-42
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