Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity

Title:Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity

Volume: 18 Issue: 5

Author(s): Anne Kasus-Jacobi*, Jennifer L. Washburn, Craig A. Land and Heloise Anne Pereira

Affiliation:

• Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK,United States

Keywords: Alzheimer's disease, amyloid beta, neutrophil, amyloid beta degrading enzyme, bioactive peptide, 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.

Cite this article as:

Kasus-Jacobi Anne *, Washburn L. Jennifer, Land A. Craig and Pereira Anne Heloise, Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity, Current Alzheimer Research 2021; 18 (5) . https://dx.doi.org/10.2174/1567205018666210823095044