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Research Article | Open Access

Sulfuretin exerts diversified functions in the processing of amyloid precursor protein

Jian Chena,1, Biao Luoa,1, Bi-Rou Zhonga, Kun-Yi Lia, Qi-Xin Wena, Li Songa, Xiao-Jiao Xianga, Gui-Feng Zhoua, Li-Tian Hua,b, Xiao-Juan Denga, Yuan-Lin Maa, Guo-Jun Chena( )
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, PR China
Department of Neurology, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, PR China

1 Jian Chen and Biao Luo contributed equally to this work.]]>

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Abstract

Sulfuretin is a flavonoid that protects cell from damage induced by reactive oxygen species and inflammation. In this study, we investigated the role of sulfuretin in the processing of amyloid precursor protein (APP), in association with the two catalytic enzymes the α-secretase a disintegrin and metalloproteinase (ADAM10), and the beta-site APP cleaving enzyme 1 (BACE1) that play important roles in the generation of β amyloid protein (Aβ) in Alzheimer's disease (AD). We found that sulfuretin increased the levels of the immature but not the mature form of ADAM10 protein. The enhanced ADAM10 transcription by sulfuretin was mediated by the nucleotides −444 to −300 in the promoter region, and was attenuated by silencing or mutation of transcription factor retinoid X receptor (RXR) and by GW6471, a specific inhibitor of peroxisome proliferator-activated receptor α (PPAR-α). We further found that sulfuretin preferentially increased protein levels of the immature form of APP (im-APP) but significantly reduced those of BACE1, sAPPβ and β-CTF, whereas Aβ1-42 levels were slightly increased. Finally, the effect of sulfuretin on BACE1 and im-APP was selectively attenuated by the translation inhibitor cycloheximide and by lysosomal inhibitor chloroquine, respectively. Taken together, (1) RXR/PPAR-α signaling was involved in sulfuretin-mediated ADAM10 transcription. (2) Alteration of Aβ protein level by sulfuretin was not consistent with that of ADAM10 and BACE1 protein levels, but was consistent with the elevated level of im-APP protein, suggesting that im-APP, an isoform mainly localized to trans-Golgi network, plays an important role in Aβ generation.

Keywords

BACE1ADAM10AβImmature APPRXR/PPAR-αSulfuretinTrans-Golgi network

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Genes & Diseases
Volume 8 Issue 6,
November 2021
Pages 867-881
DOI: 10.1016/j.gendis.2020.11.008
Cite this article:
Chen J, Luo B, Zhong B-R, et al. Sulfuretin exerts diversified functions in the processing of amyloid precursor protein. Genes & Diseases, 2021, 8(6): 867-881. https://doi.org/10.1016/j.gendis.2020.11.008

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Received: 21 July 2020
Revised: 14 November 2020
Accepted: 16 November 2020
Published: 21 November 2020
© 2020, Chongqing Medical University. Production and hosting by Elsevier B.V.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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