Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity

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

Journal Name: Current Alzheimer Research

Volume 18 , Issue 5 , 2021


Become EABM
Become Reviewer
Call for Editor

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 Aβ1-42, a central player in AD pathogenesis. CAP37, CG, and NE are serine proteases that can cleave Aβ1-42 at different sites and with different catalytic activities.

Objective: In this study, we compared the effects of these three proteins on Aβ1-42 fibrillation and neurotoxicity.

Methods: Using mass spectrometry and in vitro aggregation assay, we found that NE and CG efficiently cleave Aβ1-42. This cleavage correlates well with the inhibition of Aβ1-42 aggregation into fibrils. In contrast, CAP37 did not efficiently cleave Aβ1-42, but was still able to inhibit its fibrillation, most likely through a quenching effect. Inhibition of Aβ1-42 aggregation by NE and CG neutralized its toxicity measured in cultured neurons. In contrast, inhibition of Aβ1-42 aggregation by CAP37 did not inhibit its neurotoxicity.

Results: We found that a peptide derived from CAP37 could mimic the quenching and inhibition of Aβ1-42 aggregation effects of the full-length protein. Additionally, this peptide was able to inhibit the neurotoxicity of the most toxic Aβ1-42 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 Aβ1-42 aggregation and neurotoxicity and open up a possible strategy for the discovery of new disease-modifying drugs for AD.

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

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 18
ISSUE: 5
Year: 2021
Published on: 22 August, 2021
Page: [414 - 427]
Pages: 14
DOI: 10.2174/1567205018666210823095044
Price: $95

Article Metrics

PDF: 134