|
KMID : 1100220050040010028
|
|
Dementia and Neurocognitive Disorders
2005 Volume.4 No. 1 p.28 ~ p.34
|
|
|
Identification of BACE1 Promoter Sequence and Its Regulation by STAT1
|
|
Cho Hyun-Jin
Lee Ji-Yeon
Mook In-Hee
|
|
|
Abstract
|
|
|
Background: Beta amyloid (Aβ) peptide is one of the major causes in the pathogenesis of Alzheimer’s disease (AD). Aβ is derived from amyloid precursor protein (APP) with sequential cleavages by β-secretase (BACE1) and r-secretase. BACE1 is mainly expressed in neurons in the brain. We have previously reported that interferon-r (IFN-r ) stimulates BACE1 expression in astrocytes, which is mediated by JAK/STAT signaling pathway.
Methods: In the present study, a putative BACE1 promoter was cloned and the relationship between BACE1 promoter and STAT1 was examined using luciferase activity assay. Since the BACE1 promoter region contains a putative STAT1 binding sequence, we performed EMSA assay to examine whether STAT1 binds to the BACE1 promoter directly.
Results: The BACE1 promoter was down-regulated by an inhibitor of JAK/STAT signaling, AG490, in a dose dependent manner, which was recovered by the expression of wild type STAT1. The expression of a dominant negative mutant of STAT1 suppressed the BACE1 promoter activity, which was rescued by transfection of wild type STAT1. EMSA assay showed that STAT1 indeed binds to the BACE1 promoter. We also found that the phosphorylated form of STAT1 protein was not located in cytosolic, but in nuclear fraction.
Conclusions: Taken together, the present results suggest that IFN-r stimulates JAK/STAT signaling pathway and that phosphorylated STAT1 enters the nucleus and directly binds to the BACE1 promoter region to modulate BACE1 expression. This may be a link between brain inflammation and Aβ generation in AD.
|
|
|
KEYWORD
|
|
|
Aβ, Astrocyte, BACE1, IFN-r, Promoter, JAK/STAT
|
|
|
FullTexts / Linksout information
|
|
|
|
|
Listed journal information
|
|
 
|
|