Affiliations: [a] Discipline of Genetics, School of Molecular and Biomedical Sciences, The University of Adelaide, SA, Australia | [b] School of Medicine and Pharmacology, University of Western Australia, Level 4, Medical Research Foundation Building Rear, Perth, WA, Australia | [c] Discipline of Pharmacology, School of Medical Sciences, The University of Adelaide, SA, Australia
Correspondence:
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Correspondence to: Seyyed Hani Moussavi Nik, Discipline of Genetics, School of Molecular and Biomedical Sciences, The University of Adelaide, SA 5005, Australia. Tel.: +61 8 8303 4863; Fax: +61 8 8303 4362; E-mail: [email protected].
Abstract: Oxygen homeostasis is essential for the development and normal physiology of an organism. Hypoxia causes the mitochondrial electron transport chain to generate higher levels of reactive oxygen species resulting in oxidative stress. Hypoxia can be a direct consequence of hypoperfusion, a common vascular component among Alzheimer's disease (AD) risk factors, and may play an important role in AD pathogenesis. Beta-site amyloid-β A4 precursor protein-cleaving enzyme 1 (BACE1) is responsible, with γ-secretase, for cleavage of the amyloid-β protein precursor (AβPP) to produce amyloid-β (Aβ) peptide. A recent study observed that oxidative stress increases BACE1 expression via a regulatory pathway dependent on γ-secretase cleavage of AβPP and this increases Aβ peptide production. Zebrafish embryos represent normal cells in which complex and subtle manipulations of gene activity can be performed to facilitate analysis of genes involved in human disease. Here we identify and describe the expression of bace1, the zebrafish ortholog of human BACE1. We observe that the zebrafish AD-related genes bace1, psen1, psen2, appa, and appb all show increased mRNA levels under hypoxia. A dominant negative form of psen1 putatively blocking γ-secretase activity blocks bace1 upregulation under hypoxia. Hypoxia increases catalase gene mRNA indicating increased oxidative stress but we did not observe increased levels of F2-isoprostanes that indicate peroxidation of arachidonic acid, possibly due to relatively low levels of arachidonic acid in zebrafish. Our results demonstrate that upregulation of PSEN1 & 2, AβPP and the γ-secretase-dependent upregulation of BACE1 is an ancient, conserved, and thus selectively advantageous response to hypoxia/oxidative stress.
