Anne Kasus-Jacobi*, Jennifer L. Washburn, Craig A. Land and Heloise Anne Pereira Pages 414 - 427 ( 14 )
<P>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<sub>1-42</sub>, a central player in AD pathogenesis. CAP37, CG, and NE are serine proteases that can cleave Aβ<sub>1-42</sub> at different sites and with different catalytic activities. </P><P> Objective: In this study, we compared the effects of these three proteins on Aβ<sub>1-42</sub> fibrillation and neurotoxicity. </P><P> Methods: Using mass spectrometry and in vitro aggregation assay, we found that NE and CG efficiently cleave Aβ<sub>1-42</sub>. This cleavage correlates well with the inhibition of Aβ<sub>1-42</sub> aggregation into fibrils. In contrast, CAP37 did not efficiently cleave Aβ<sub>1-42</sub>, but was still able to inhibit its fibrillation, most likely through a quenching effect. Inhibition of Aβ<sub>1-42</sub> aggregation by NE and CG neutralized its toxicity measured in cultured neurons. In contrast, inhibition of Aβ<sub>1-42</sub> aggregation by CAP37 did not inhibit its neurotoxicity. </P><P> Results: We found that a peptide derived from CAP37 could mimic the quenching and inhibition of Aβ<sub>1-42</sub> aggregation effects of the full-length protein. Additionally, this peptide was able to inhibit the neurotoxicity of the most toxic Aβ<sub>1-42</sub> aggregate, an effect that was not found with the full-length CAP37. </P><P> Conclusion: These results shed light on the mechanisms of action of neutrophil granule proteins with regard to inhibition of Aβ<sub>1-42</sub> aggregation and neurotoxicity and open up a possible strategy for the discovery of new disease-modifying drugs for AD.</P>
Alzheimer's disease, amyloid beta, neutrophil, amyloid beta degrading enzyme, bioactive peptide, neurotoxicity.
Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK