Peptide‐Modified Mo Polyoxometalate Nanoparticles Suppress Zn²⁺‐Induced Aβ Aggregation

Abstract

The abnormal metabolism of amyloid‐β (Aβ) peptide, as one of the main components of senile plaques, plays a vital role in the pathogenesis of Alzheimer's disease (AD). Our previous work showed that polyoxometalates (POMs) that inhibited the formation of Aβ aggregates were promising for AD therapy. Here, peptide‐modified Mo polyoxometalate (Mo‐POMs) nanoparticles were synthesized by the self‐assembly of Aβ target peptide and Mo‐POMs based on our previous work. Importantly, after modifying with the Aβ target peptide, the Mo polyoxometalate (Mo‐POMs) nanoparticles exhibited enhanced blood‐brain barrier (BBB) penetration and high binding affinity with Aβ species. The interactions between the Peptide@Mo‐POMs nanoparticle and Aβ in the presence of Zn2+ were comprehensively studied using physicochemical methods (spectroscopy, ThT fluorescence, turbidity tests). Peptide@Mo‐POMs could suppress Aβ aggregation, disaggregate Aβ fibrils, and suppress Zn2+‐induced Aβ aggregation. In addition, in vitro cell experiments revealed that Peptide@Mo‐POMs could target and be well absorbed by PC12 cells, leading to the inhibition of intracellular Aβ aggregation and reduced Aβ aggregates‐induced cytotoxicity. The blood‐brain barrier (BBB) permeability of Peptide@Mo‐POMs was also revealed by the Transwell experiment. This study gives a mechanistic understanding into how Peptide@Mo‐POMs can work through a synergistic interaction with metal ions and Aβ, and provides new insights into the design and synthesis of POMs as Aβ inhibitors in the treatment of AD.

Promising application of polyoxometalates in the treatment of cancer, infectious diseases and Alzheimer’s disease

“…The results show that POMs could significantly improve the cell survival rate, inhibit Aβ aggregation and reduce the cytotoxicity induced by Aβ [95,96]. Similarly, peptide-modified Mo-POM nanoparticles have been synthesized by the selfassembly of Aβ target peptides and Mo-POMs [100]. The Peptide@Mo-POMs suppress Aβ aggregation, disaggregate Aβ fibrils, and suppress Zn 2+ -induced Aβ aggregation.…”

Rational Design and Self-Assembly of Polyoxometalate-Peptide Hybrid Materials

“…This hexapeptide contains the "recognition element" KLVFF, a fragment of the native amyloid-b peptide which can bind to the full length peptide and prevent its aggregation. 81,82 Two different types of POMs have been used to form POM@Aβ15-20 hybrids: a Wells-Dawson 56 and a polyoxomolybdate 70 . Again, in the first step, the peptides and POMs bind by electrostatic interaction to form peptide-encapsulated clusters which can further stack into supramolecular networks.…”

Recent Progress in Ionic Coassembly of Cationic Peptides and Anionic Species

“…[ 266 ] This work was followed by Liu and co‐workers. [ 267 ] More interestingly, the photochemical property of POMs has been explored as photocatalysts to degrade not only the Aβ monomers but also the oligomers, leading to the enhanced inhibition ( Figure ). [ 268 ] Exemplifying this, they used in vitro thioflavin T (ThT) fluorescence assay to verify the effects of POMs on Aβ aggregation with or without photoirradiation.…”