Forkhead box O1 (FoxO1), a key molecule in the regulation of cell growth, differentiation and metabolism, is an important transcription factor. However, the effect of FoxO1 on Alzheimer’s disease (AD) needs further investigation. In this study, we aimed to explore the function and mechanism of FoxO1 in amyloid-β (Aβ) production and tau phosphorylation in AD. First, compared with the age matched wild-type (WT) mice, we showed that FoxO1 protein levels were reduced in the cortices but nearly unchanged in the hippocampi of 6-month-old APPswe/PSEN1dE9 transgenic mice expressing Swedish APP and Presenilin1 delta exon 9 mutations (APP/PS1 mice). Then, we found that overexpression of FoxO1 significantly attenuated Aβ production through inhibiting the amyloidogenic processing of β-amyloid precursor protein (APP), mediated by the key enzymes BACE1 and PS1, in N2a/APPsw cells. Furthermore, in FoxO1-overexpressing HEK293/Tau cells, the decreased levels of tau phosphorylation at selective sites (S262 and T231) were accompanied by increasing the expression of p-GSK-3β (S9), and reducing p-ERK. In contrast, the total tau (Tau-5), non-phosphorylated tau (Tau-1), p-Tau (S404), CDK5 and PP2A levels remained unchanged. These findings indicate that FoxO1 is related to AD and suggest FoxO1 as a therapeutic target for AD that reduces the levels of both Aβ expression and tau phosphorylation.

叉头箱O1（FoxO1）是调节细胞生长，分化和代谢的关键分子，是重要的转录因子。但是，FoxO1对阿尔茨海默氏病（AD）的作用需要进一步研究。在这项研究中，我们旨在探讨FoxO1在AD中淀粉样β（Aβ）产生和tau磷酸化中的功能和机制。首先，与年龄匹配的野生型（WT）小鼠相比，我们发现表达瑞典APP和Presenilin1 delta外显子的6个月大APPswe / PSEN1dE9转基因小鼠的皮质中FoxO1蛋白水平降低，但海马体中几乎不变。 9个突变（APP / PS1小鼠）。然后，我们发现FoxO1的过表达通过抑制由关键酶BACE1和PS1介导的β淀粉样蛋白前体蛋白（APP）的淀粉样蛋白生成过程而显着减弱了Aβ的产生，在N2a / APPsw细胞中。此外，在过表达FoxO1的HEK293 / Tau细胞中，选择性位点（S262和T231）上tau磷酸化水平的降低伴随着p-GSK-3β（S9）表达的增加和p-ERK的降低。相反，总tau（Tau-5），非磷酸化tau（Tau-1），p-Tau（S404），CDK5和PP2A水平保持不变。这些发现表明FoxO1与AD有关，并暗示FoxO1作为AD的治疗靶标，其降低了Aβ表达和tau磷酸化水平。CDK5和PP2A水平保持不变。这些发现表明FoxO1与AD有关，并暗示FoxO1作为AD的治疗靶标，其降低了Aβ表达和tau磷酸化水平。CDK5和PP2A水平保持不变。这些发现表明FoxO1与AD有关，并暗示FoxO1作为AD的治疗靶标，其降低了Aβ表达和tau磷酸化水平。