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J. Biol. Chem., Vol. 282, Issue 15, 10873-10880, April 13, 2007

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Hypoxia-inducible Factor 1 (HIF-1)-mediated Hypoxia Increases BACE1 Expression and -Amyloid Generation^*

Xian Zhang¹, Kun Zhou^¶1, Ruishan Wang, Jiankun Cui, Stuart A. Lipton, Francesca-Fang Liao, Huaxi Xu², and Yun-wu Zhang³

From the Institute for Biomedical Research and School of Life Sciences, Xiamen University, Xiamen 361005, China, the ^¶Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and the Burnham Institute for Medical Research, La Jolla, California 92037

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. -Amyloid peptide (A), which is derived from the -amyloid precursor protein (APP) by sequential proteolytic cleavages from -secretase (BACE1) and presenilin-1 (PS1)/-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- (CTF) and A. Hypoxia has no effect on the level of PS1, APP, and tumor necrosis factor--converting enzyme (TACE, an enzyme known to cleave APP at the -secretase cleavage site). Sequence analysis, mutagenesis, and gel shift studies revealed binding of HIF-1 to the BACE1 promoter. Overexpression of HIF-1 increases BACE1 mRNA and protein level, whereas down-regulation of HIF-1 reduced the level of BACE1. Hypoxic treatment fails to further potentiate the stimulatory effect of HIF-1 overexpression on BACE1 expression, suggesting that hypoxic induction of BACE1 expression is primarily mediated by HIF-1. Finally, we observed significant reduction in BACE1 protein levels in the hippocampus and the cortex of HIF-1 conditional knock-out mice. Our results demonstrate an important role for hypoxia/HIF-1 in modulating the amyloidogenic processing of APP and provide a molecular mechanism for increased incidence of AD following cerebral ischemic and stroke injuries.

Received for publication, September 14, 2006 , and in revised form, January 22, 2007.

Note Added in Revision—While this manuscript was under review, an article by Sun et al. was published in Proc. Natl. Acad. Sci. U. S. A. (48) reporting a functional hypoxia-responsive element in the BACE1 gene promoter and that hypoxia can increase BACE1 transcription and expression leading to increased APP processing and A generation.

^* This work was supported in part by National Institutes of Health Grants R01 AG030197, R01 NS046673, and R01 AG021173 (to H. X.) and R01 NS054880 (to F. F. L.), and grants from the Alzheimer Association (to H. X.), the American Health Assistance Foundation (to H. X.), and the National Natural Science Foundation of China (No. 30672198, to Y.-w. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this study and share first authorship.

³ Recipient of National Institutes of Health Training Grant F32 AG024895. To whom correspondence may be addressed: Burnham Institute for Medical Research, La Jolla, CA 92037. Tel.: 858-795-5246; Fax: 858-795-5273; E-mail: yunzhang{at}burnham.org.

² To whom correspondence may be addressed: Burnham Institute for Medical Research, La Jolla, CA 92037. Tel.: 858-795-5246; Fax: 858-795-5273; E-mail: xuh{at}burnham.org.

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