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Hypoxia-inducible Factor 1α (HIF-1α)-mediated Hypoxia Increases BACE1 Expression and β-Amyloid Generation
Open accessAbstract
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 (Abeta), 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 (betaCTF) and Abeta. 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-1alpha increases BACE1 mRNA and protein level, whereas down-regulation of HIF-1alpha reduced the level of BACE1. Hypoxic treatment fails to further potentiate the stimulatory effect of HIF-1alpha overexpression on BACE1 expression, suggesting that hypoxic induction of BACE1 expression is primarily mediated by HIF-1alpha. Finally, we observed significant reduction in BACE1 protein levels in the hippocampus and the cortex of HIF-1alpha conditional knock-out mice. Our results demonstrate an important role for hypoxia/HIF-1alpha in modulating the amyloidogenic processing of APP and provide a molecular mechanism for increased incidence of AD following cerebral ischemic and stroke injuries.
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“BACE1 levels and activity increase in response to hypoxia, energy disruption, and mitochondrial stress, owing to HIF‐1 binding the BACE1 promoter.”
From BACE1: More than just a β‐secretase (2022) · cites this paper as [49]
In the citing paper
“reduced blood flow increases Aβ production (13, 14).”
From Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes (2019) · cites this paper as [14]
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Metadata
- Authors
- Zhang, X., Zhou, K., Wang, R., Cui, J., Lipton, S. A., Liao, F.-F., Xu, H., & Zhang, Y.-W.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Xu, Huaxi
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-04
- Volume
- 282
- Issue
- 15
- Pages
- 10873-10880
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2030333049
- Semantic Scholar
- eb4c044d3442f536df662e6d66780f400d3ccdf9
- Cited by
- 436
- References
- 48
- Citations by year
- 2026: 22 · 2025: 27 · 2024: 26 · 2023: 18 · 2022: 23 · 2021: 23 · 2020: 13 · 2019: 16 · 2018: 24 · 2017: 15 · 2016: 20 · 2015: 28 · 2014: 34 · 2013: 22 · 2012: 29
- FWCI
- 14.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG030197, R01 AG021173)
- National Institute of Neurological Disorders and Stroke (R01NS046673, R01NS054880)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- hypoxia, HIF-1α, BACE1, amyloid-beta, Alzheimer's disease, vascular dementia, APP processing, beta-secretase, cerebral ischemia, stroke, hippocampus, cerebral cortex
- MeSH terms
- Animals, Base Sequence, Binding Sites, Brain, Cell Line, Humans, Molecular Sequence Data, Promoter Regions, Genetic, Time Factors, Transcription, Genetic, Cell Hypoxia, Up-Regulation, Gene Expression Regulation, Enzymologic, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice, Knockout, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Amyloid Precursor Protein Secretases
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