The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the predominant β-secretase, cleaving the amyloid precursor protein (APP) the amyloidogenic pathway. In addition, BACE1 as an amyloid degrading enzyme (ADE), cleaves Aβ to produce the C-terminally truncated non-toxic Aβ fragment Aβ34 which is an indicator of amyloid clearance. Here, we analyzed the effects of BACE1 inhibitors on its opposing enzymatic functions, , amyloidogenic (Aβ producing) and amyloidolytic (Aβ degrading) activities, using cell culture models with varying BACE1/APP ratios. Under high-level BACE1 expression, low-dose inhibition unexpectedly yielded a two-fold increase in Aβ42 and Aβ40 levels. The concomitant decrease in Aβ34 and secreted APPβ levels suggested that the elevated Aβ42 and Aβ40 levels were due to the attenuated Aβ degrading activity of BACE1. Notably, the amyloidolytic activity of BACE1 was impeded at lower BACE1 inhibitor concentrations compared to its amyloidogenic activity, thereby suggesting that the Aβ degrading activity of BACE1 was more sensitive to inhibition than its Aβ producing activity. Under endogenous BACE1 and APP levels, “low-dose” BACE1 inhibition affected both the Aβ producing and degrading activities of BACE1, , significantly increased Aβ42/Aβ40 ratio and decreased Aβ34 levels, respectively. Further, we incubated recombinant BACE1 with synthetic Aβ peptides and found that BACE1 has a higher affinity for Aβ substrates over APP. In summary, our results suggest that stimulating BACE1’s ADE activity and halting Aβ production without decreasing Aβ clearance could still be a promising therapeutic approach with new, yet to be developed, BACE1 modulators.

中文翻译：

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BACE1 的抑制会影响其 Aβ 产生和降解活性，并在 BACE1 高水平表达时增加 Aβ42 和 Aβ40 水平


β 位点淀粉样前体蛋白裂解酶 1 (BACE1) 是主要的 β-分泌酶，可裂解淀粉样前体蛋白 (APP) 的淀粉样蛋白生成途径。此外，BACE1 作为淀粉样蛋白降解酶 (ADE)，可裂解 Aβ，产生 C 端截短的无毒 Aβ 片段 Aβ34，这是淀粉样蛋白清除的指标。在这里，我们使用不同 BACE1/APP 比例的细胞培养模型分析了 BACE1 抑制剂对其相反酶功能、淀粉样蛋白生成（Aβ 产生）和淀粉样蛋白分解（Aβ 降解）活性的影响。在高水平 BACE1 表达下，低剂量抑制意外地使 Aβ42 和 Aβ40 水平增加两倍。 Aβ34 和分泌的 APPβ 水平随之下降表明 Aβ42 和 Aβ40 水平升高是由于 BACE1 的 Aβ 降解活性减弱。值得注意的是，与淀粉样蛋白生成活性相比，BACE1 的淀粉样蛋白分解活性在较低的 BACE1 抑制剂浓度下受到阻碍，从而表明 BACE1 的 Aβ 降解活性比其 Aβ 产生活性对抑制更敏感。在内源性 BACE1 和 APP 水平下，“低剂量”BACE1 抑制影响 BACE1 的 Aβ 产生和降解活性，分别显着增加 Aβ42/Aβ40 比率和降低 Aβ34 水平。此外，我们将重组 BACE1 与合成 Aβ 肽一起孵育，发现 BACE1 对 Aβ 底物的亲和力比 APP 更高。总之，我们的结果表明，使用尚未开发的新 BACE1 调节剂，刺激 BACE1 的 ADE 活性并停止 Aβ 产生而不降低 Aβ 清除率仍然是一种有前途的治疗方法。