TY - JOUR
T1 - Activation of liver x receptor decreases BACE1 expression and activity by reducing membrane cholesterol levels
AU - Cui, Weigang
AU - Sun, Yan
AU - Wang, Zhongping
AU - Xu, Chongchong
AU - Xu, Li
AU - Wang, Fei
AU - Chen, Zulin
AU - Peng, Yuwen
AU - Li, Ruixi
PY - 2011/10
Y1 - 2011/10
N2 - The synthetic Liver X receptor (LXR) activator T0901317 has been reported to exert neuroprotective effect in Alzheimer's disease, but the relationship between LXR activation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) remains uncertain. This study investigated the effect of T0901317 on membrane cholesterol levels, BACE1 expression and activity. We found that T0901317 decreased membrane cholesterol levels, reduced BACE1 expression and activity as well as b-secretase cleaved C-terminal fragment (b-CTF) levels in vivo and in vitro. Meanwhile, the expression of ATP-binding membrane cassette transport protein A1 (ABCA1) enhanced. Additionally, inhibition of ABCA1 abrogated the effects of T0901317 on membrane cholesterol levels and b-secretase activity. Moreover, addition of LXR antagonist reversed the effect of T0901317 on ABCA1 mRNA expression, membrane cholesterol levels and b-secretase activity. Our results suggest that activation of LXR may decrease BACE1 expression and activity through a pathway associated with ABCA1-mediated reduction in membrane cholesterol levels.
AB - The synthetic Liver X receptor (LXR) activator T0901317 has been reported to exert neuroprotective effect in Alzheimer's disease, but the relationship between LXR activation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) remains uncertain. This study investigated the effect of T0901317 on membrane cholesterol levels, BACE1 expression and activity. We found that T0901317 decreased membrane cholesterol levels, reduced BACE1 expression and activity as well as b-secretase cleaved C-terminal fragment (b-CTF) levels in vivo and in vitro. Meanwhile, the expression of ATP-binding membrane cassette transport protein A1 (ABCA1) enhanced. Additionally, inhibition of ABCA1 abrogated the effects of T0901317 on membrane cholesterol levels and b-secretase activity. Moreover, addition of LXR antagonist reversed the effect of T0901317 on ABCA1 mRNA expression, membrane cholesterol levels and b-secretase activity. Our results suggest that activation of LXR may decrease BACE1 expression and activity through a pathway associated with ABCA1-mediated reduction in membrane cholesterol levels.
KW - Alzheimer's disease
KW - BACE1
KW - Beta-amyloid
KW - Liver X receptor
KW - Membrane cholesterol
UR - https://www.scopus.com/pages/publications/80555155558
U2 - 10.1007/s11064-011-0513-3
DO - 10.1007/s11064-011-0513-3
M3 - 文章
C2 - 21630010
AN - SCOPUS:80555155558
SN - 0364-3190
VL - 36
SP - 1910
EP - 1921
JO - Neurochemical Research
JF - Neurochemical Research
IS - 10
ER -