Dataset Information

Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity.

ABSTRACT:

Background

A role for neutrophils in the pathogenesis of Alzheimer's disease (AD) is emerging. We previously showed that the neutrophil granule proteins cationic antimicrobial protein of 37 kDa (CAP37), cathepsin G (CG), and neutrophil elastase (NE) directly bind the amyloid-beta peptide Aβ_1-42, a central player in AD pathogenesis. CAP37, CG, and NE are serine proteases that can cleave Aβ_1-42 at different sites and with different catalytic activities.

Objective

In this study, we compared the effects of these three proteins on Aβ_1-42 fibrillation and neurotoxicity.

Methods

Using mass spectrometry and in vitro aggregation assay, we found that NE and CG efficiently cleave Aβ_1-42. This cleavage correlates well with the inhibition of Aβ_1-42 aggregation into fibrils. In contrast, CAP37 did not efficiently cleave Aβ_1-42, but was still able to inhibit its fibrillation, most likely through a quenching effect. Inhibition of Aβ_1-42 aggregation by NE and CG neutralized its toxicity measured in cultured neurons. In contrast, inhibition of Aβ_1-42 aggregation by CAP37 did not inhibit its neurotoxicity.

Results

We found that a peptide derived from CAP37 could mimic the quenching and inhibition of Aβ_1-42 aggregation effects of the full-length protein. Additionally, this peptide was able to inhibit the neurotoxicity of the most toxic Aβ_1-42 aggregate, an effect that was not found with the full-length CAP37.

Conclusion

These results shed light on the mechanisms of action of neutrophil granule proteins with regard to inhibition of Aβ_1-42 aggregation and neurotoxicity and open up a possible strategy for the discovery of new disease-modifying drugs for AD.

SUBMITTER: Kasus-Jacobi A

PROVIDER: S-EPMC9791948 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity.

Kasus-Jacobi Anne A Washburn Jennifer L JL Land Craig A CA Pereira Heloise Anne HA

Current Alzheimer research 20210101 5

<h4>Background</h4>A role for neutrophils in the pathogenesis of Alzheimer's disease (AD) is emerging. We previously showed that the neutrophil granule proteins cationic antimicrobial protein of 37 kDa (CAP37), cathepsin G (CG), and neutrophil elastase (NE) directly bind the amyloid-beta peptide Aβ<sub>1-42</sub>, a central player in AD pathogenesis. CAP37, CG, and NE are serine proteases that can cleave Aβ<sub>1-42</sub> at different sites and with different catalytic activities.<h4>Objective</ ...[more]

PMID: 34429047

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Project description:The misfolding and aggregation of amyloid-β (Aβ) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of Aβ1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against Aβ-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent Aβ peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic β-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-Aβ and TS2-Aβ systems also interpret different inhibitory effects on Aβ aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of Aβ inhibitors to prevent and disaggregate amyloid formation.

Dataset Information

Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity.

Background

Objective

Methods

Results

Conclusion

Publications

Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity.

Similar Datasets

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