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

被引:370
作者
Zhang, Xian [1 ]
Zhou, Kun
Wang, Ruishan
Cui, Jiankun
Lipton, Stuart A.
Liao, Francesca-Fang
Xu, Huaxi
Zhang, Yun-wu
机构
[1] Burnham Inst Med Res, La Jolla, CA 92037 USA
[2] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Shanghai 200025, Peoples R China
[3] Shanghai Jiao Tong Univ, Sch Med, Shanghai 200025, Peoples R China
[4] Xiamen Univ, Inst Biomed Res, Xiamen 361005, Peoples R China
[5] Xiamen Univ, Sch Life Sci, Xiamen 361005, Peoples R China
关键词
D O I
10.1074/jbc.M608856200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 [生物化学与分子生物学]; 081704 [应用化学];
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.
引用
收藏
页码:10873 / 10880
页数:8
相关论文
共 47 条
[1]
Accelerated accumulation of N- and C-terminal βAPP fragments and delayed recovery of microtubule-associated protein 1B expression following stroke in aged rats [J].
Badan, I ;
Dinca, I ;
Buchhold, B ;
Suofu, Y ;
Walker, L ;
Gratz, M ;
Platt, D ;
Kessler, CH ;
Popa-Wagner, A .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2004, 19 (08) :2270-2280
[2]
Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor [J].
Buxbaum, JD ;
Liu, KN ;
Luo, YX ;
Slack, JL ;
Stocking, KL ;
Peschon, JJ ;
Johnson, RS ;
Castner, BJ ;
Cerretti, DP ;
Black, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (43) :27765-27767
[3]
PROCESSING OF ALZHEIMER BETA-A4 AMYLOID PRECURSOR PROTEIN - MODULATION BY AGENTS THAT REGULATE PROTEIN-PHOSPHORYLATION [J].
BUXBAUM, JD ;
GANDY, SE ;
CICCHETTI, P ;
EHRLICH, ME ;
CZERNIK, AJ ;
FRACASSO, RP ;
RAMABHADRAN, TV ;
UNTERBECK, AJ ;
GREENGARD, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (15) :6003-6006
[4]
BACE1 is the major β-secretase for generation of Aβ peptides by neurons [J].
Cai, HB ;
Wang, YS ;
McCarthy, D ;
Wen, HJ ;
Borchelt, DR ;
Price, DL ;
Wong, PC .
NATURE NEUROSCIENCE, 2001, 4 (03) :233-234
[5]
Transcriptional regulation of BACE1, the β-amyloid precursor protein β-secretase, by Sp1 [J].
Christensen, MA ;
Zhou, WH ;
Qing, H ;
Lehman, A ;
Philipsen, S ;
Song, WH .
MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (02) :865-874
[6]
Chun YS, 2001, J CELL SCI, V114, P4051
[7]
BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein [J].
Farzan, M ;
Schnitzler, CE ;
Vasilieva, N ;
Leung, D ;
Choe, H .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (17) :9712-9717
[8]
Cellular and molecular basis of β-amyloid precursor protein metabolism [J].
Greenfield, JP ;
Gross, RS ;
Gouras, GK ;
Xu, HX .
FRONTIERS IN BIOSCIENCE, 2000, 5 :D72-D83
[9]
Medicine - The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics [J].
Hardy, J ;
Selkoe, DJ .
SCIENCE, 2002, 297 (5580) :353-356
[10]
Brain-specific knock-out of hypoxia-inducible factor-1α reduces rather than increases hypoxic-ischemic damage [J].
Helton, R ;
Cui, J ;
Scheel, JR ;
Ellison, JA ;
Ames, C ;
Gibson, C ;
Blouw, B ;
Ouyang, L ;
Dragatsis, I ;
Zeitlin, S ;
Johnson, RS ;
Lipton, SA ;
Barlow, C .
JOURNAL OF NEUROSCIENCE, 2005, 25 (16) :4099-4107