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.