Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity

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.