FoxO1 overexpression reduces Aβ production and tau phosphorylation in vitro. (1st November 2020)

• Record Type: Journal Article
• Authors: Zhang, Wei; Bai, Shanshan; Yang, Jianhua; Zhang, Yimin; Liu, Youcai; Nie, Junjiu; Meng, Dongli; Shi, Ruling; Yao, Zhaoyang; Wang, Mingyong; Wang, Hecheng; Li, Cuiping
• Is Part Of: Neuroscience letters. Volume 738(2020)
• Publication Date: 2020-11-01
• Subjects: Alzheimer's disease -- FoxO1 -- BACE1 -- PS1 -- tau phosphorylation -- GSK-3β; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2020.135322
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: FoxO1 reduces Aβ level by inhibiting the amyloid pathway mediated by BACE1 and PS1. FoxO1 reduces tau phosphorylation by regulating the activities of GSK-3β and ERK. FoxO1 plays a critical role in AD-like pathology and that FoxO1 is a novel target for AD treatment. Abstract: 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.