Sulfuretin exerts diversified functions in the processing of amyloid precursor protein  

作　　者：Jian Chen Biao Luo Bi-Rou Zhong Kun-Yi Li Qi-Xin Wen Li Song Xiao-Jiao Xiang Gui-Feng Zhou Li-Tian Hu Xiao-Juan Deng Yuan-Lin Ma Guo-Jun Chen 

机构地区：[1]Department of Neurology,The First Affiliated Hospital of Chongqing Medical University,Chongqing Key Laboratory of Neurology,1 Youyi Road,Chongqing,400016,PR China [2]Department of Neurology,Nanchong Central Hospital,The Second Clinical College of North Sichuan Medical College,Nanchong,Sichuan Province,637000,PR China

出　　处：《Genes & Diseases》2021年第6期867-881,共15页基因与疾病（英文）

基　　金：This work was supported by National Key R&D Program of China(2018YFC1314700)to L-J Jin;by NSFC(81971030);Chongqing Science and Technology Commission grant(cstc2018jcyjAX0067)to G-J.Chen;by The strategic science&technology cooperation Project of North Sichuan Medical College and Nanchong Municipal Government(18SXHZ0184);Scientific Research Development Project of North Sichuan Medical College(CBY17-A-ZD03);Sichuan Provincial Health and Family Planning Commission(18PJ335)to Li-Tian Hu.

摘　　要：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 a-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 nucleotides444 to300 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 Ab1-42 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 Ab generation.

关 键 词：Ab ADAM10 BACE1 Immature APP RXR/PPAR-a Sulfuretin Trans-Golgi network 

分 类 号：Q5[生物学—生物化学]