Hypoxia-inducible factor 1 alpha (HIF-1 alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation

CORC > 厦门大学 > 生物医学－已发表论文

	Hypoxia-inducible factor 1 alpha (HIF-1 alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation
	Zhang, X. ; Zhou, K. ; Wang, R. S. ; Cui, J. K. ; Lipton, S. A. ; Liao, F. F. ; Xu, H. X. ; Zhang, Y. W. ; Zhang YW(张云武)
刊名	http://dx.doi.org/10.1074/jbc.M608856200
	2007-04-13
关键词	HUMAN NEUROBLASTOMA SH-SY5Y ALPHA-SECRETASE CLEAVAGE PRECURSOR PROTEIN ALZHEIMERS-DISEASE TRANSCRIPTIONAL REGULATION CEREBRAL-ISCHEMIA INDUCIBLE FACTOR-1-ALPHA GENE-EXPRESSION MESSENGER-RNA APP
英文摘要	The incidence of Alzheimer disease (AD) and vascular dementia is greatly increased following cerebral ischemia and stroke in which hypoxic conditions occur in affected brain areas. beta-Amyloid peptide (A beta), which is derived from the beta-amyloid precursor protein (APP) by sequential proteolytic cleavages from beta-secretase (BACE1) and presenilin-1 (PS1)/gamma-secretase, is widely believed to trigger a cascade of pathological events culminating in AD and vascular dementia. However, a direct molecular link between hypoxic insults and APP processing has yet to be established. Here, we demonstrate that acute hypoxia increases the expression and the enzymatic activity of BACE1 by up-regulating the level of BACE1 mRNA, resulting in increases in the APP C-terminal fragment-beta (beta CTF) and A beta. Hypoxia has no effect on the level of PS1, APP, and tumor necrosis factor-alpha-converting enzyme (TACE, an enzyme known to cleave APP at the alpha-secretase cleavage site). Sequence analysis, mutagenesis, and gel shift studies revealed binding of HIF-1 to the BACE1 promoter. Overexpression of HIF-1 alpha increases BACE1 mRNA and protein level, whereas down-regulation of HIF-1 alpha reduced the level of BACE1. Hypoxic treatment fails to further potentiate the stimulatory effect of HIF-1 alpha overexpression on BACE1 expression, suggesting that hypoxic induction of BACE1 expression is primarily mediated by HIF-1 alpha. Finally, we observed significant reduction in BACE1 protein levels in the hippocampus and the cortex of HIF-1 alpha conditional knock-out mice. Our results demonstrate an important role for hypoxia/ HIF-1 alpha in modulating the amyloidogenic processing of APP and provide a molecular mechanism for increased incidence of AD following cerebral ischemic and stroke injuries.
语种	英语
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/66011]
专题	生物医学－已发表论文
推荐引用方式 GB/T 7714	Zhang, X.,Zhou, K.,Wang, R. S.,et al. Hypoxia-inducible factor 1 alpha (HIF-1 alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation[J]. http://dx.doi.org/10.1074/jbc.M608856200,2007.
APA	Zhang, X..,Zhou, K..,Wang, R. S..,Cui, J. K..,Lipton, S. A..,...&张云武.(2007).Hypoxia-inducible factor 1 alpha (HIF-1 alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation.http://dx.doi.org/10.1074/jbc.M608856200.
MLA	Zhang, X.,et al."Hypoxia-inducible factor 1 alpha (HIF-1 alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation".http://dx.doi.org/10.1074/jbc.M608856200 (2007).