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Sulfuretin exerts diversified functions in the processing of amyloid precursor protein

Genes & Diseases 2021年第6期8卷 867-881页

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 Department of Neurology The First Affiliated Hospital of Chongqing Medical UniversityChongqing Key Laboratory of Neurology1 Youyi RoadChongqing400016PR China Department of Neurology Nanchong Central HospitalThe Second Clinical College of North Sichuan Medical CollegeNanchongSichuan Province637000PR China

Sulfuretin is a flavonoid that protects cell from damage induced by reactive oxygen species and *** 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 *** 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 ***,the effect of sulfuretin on BACE1 and im-APP was selectively attenuated by the translation inhibitor cycloheximide and by lysosomal inhibitor chloroquine,*** 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

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