期刊
NEUROSCIENCE LETTERS
卷 738, 期 -, 页码 -出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2020.135322
关键词
Alzheimer's disease; FoxO1; BACE1; PS1; tau phosphorylation; GSK-3 beta
资金
- National Natural Science Foundation [U1604108]
- Key Science and Technology Program of Henan Province [202102310020, 202102310404, 18210231114]
- Program for Innovative Research Team (in Science and Technology) in University of Henan Province [20IRTSTHN030]
- Graduate Scientific Research Innovation Support Project of Xinxiang Medical University [YJSCX201866Y]
- Fundamental Research Funds for the Central Universities [DUT19LK36]
- Key scientific research project of higher education of Henan Province [16A310010]
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-beta (A beta) 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 A beta production through inhibiting the amyloidogenic processing of beta-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-3 beta (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 A beta expression and tau phosphorylation.
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