γ-Secretase inhibitors have been considered promising drug candidates against Alzheimer's disease (AD) due to their ability to reduce amyloid-β (Aβ) production. However, clinical trials have been halted due to lack of clinical efficacy and/or side effects. Recent in vitro studies suggest that low doses of γ-secretase inhibitors may instead increase Aβ production. Using a stem cell-derived human model of cortical neurons and low doses of the γ-secretase inhibitor DAPT, the effects on a variety of Aβ peptides were studied using mass spectrometry. One major focus was to develop a novel method for specific detection of oligomeric Aβ (oAβ), and this was used to study the effects of low-dose γ-secretase inhibitor treatment on intracellular oAβ accumulation. Low-dose treatment (2 and 20 nM) with DAPT increased the secretion of several Aβ peptides, especially Aβx-42. Furthermore, using the novel method for oAβ detection, we found that 2 nM DAPT treatment of cortical neurons resulted in increased oAβ accumulation. Thus, low dose-treatment with DAPT causes both increased production of long, aggregation-prone Aβ peptides and accumulation of intracellular Aβ oligomers, both believed to contribute to AD pathology.

γ-分泌酶抑制剂由于其减少淀粉样β（Aβ）产生的能力而被认为是对抗阿尔茨海默氏病（AD）的有前途的候选药物。然而，由于缺乏临床功效和/或副作用，临床试验已经停止。最近的体外研究表明，低剂量的γ-分泌酶抑制剂可能反而会增加Aβ的产生。使用源自干细胞的皮质神经元人类模型和低剂量的γ-分泌酶抑制剂DAPT，使用质谱研究了对多种Aβ肽的影响。一个主要重点是开发一种特异性检测寡聚Aβ（oAβ）的新方法，该方法用于研究低剂量γ-分泌酶抑制剂治疗对细胞内oAβ积累的影响。DAPT的低剂量治疗（2和20 nM）增加了几种Aβ肽，尤其是Aβx-42的分泌。此外，使用新颖的oAβ检测方法，我们发现2 nM DAPT处理皮质神经元会导致oAβ积累增加。因此，DAPT的低剂量治疗会导致长效，