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.

背景：嗜中性粒细胞在阿尔茨海默病 (AD) 发病机制中的作用正在显现。我们之前表明，37 kDa (CAP37) 的中性粒细胞颗粒蛋白阳离子抗菌蛋白、组织蛋白酶 G (CG) 和中性粒细胞弹性蛋白酶 (NE) 直接结合淀粉样蛋白-β 肽 Aβ _1-42，后者是 AD 发病机制的核心参与者。CAP37、CG和NE是丝氨酸蛋白酶，可以在不同位点切割_Aβ1-42，具有不同的催化活性。

目的：在本研究中，我们比较了这三种蛋白质对 Aβ _1-42原纤维颤动和神经毒性的影响。

方法：使用质谱法和体外聚集试验，我们发现 NE 和 CG 可有效切割 Aβ _1-42。这种切割与抑制 Aβ _1-42聚集成原纤维密切相关。相反，CAP37 不能有效地切割 Aβ _1-42，但仍然能够抑制其纤维化，很可能是通过猝灭效应。NE 和 CG对 Aβ _1-42聚集的抑制中和了其在培养的神经元中测得的毒性。相反，CAP37 对 Aβ _1-42聚集的抑制不会抑制其神经毒性。

结果：我们发现源自 CAP37 的肽可以模拟全长蛋白对 Aβ _{1-42聚集效应的淬灭和抑制。}此外，该肽能够抑制毒性最强的 Aβ _1-42聚集体的神经毒性，而全长 CAP37 未发现这种作用。

结论：这些结果阐明了中性粒细胞颗粒蛋白在抑制 Aβ _1-42聚集和神经毒性方面的作用机制，并为发现新的 AD 疾病缓解药物开辟了一条可能的策略。