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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 effi- ciently cleave Aβ1-42. This cleavage correlates well with the inhibition of Aβ1-42 aggregation into fi- brils. 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.