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
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.
