The BACE1-PSEN-AβPP regulatory axis has an ancient role in response to low oxygen/oxidative stress

Discipline of Genetics, School of Molecular and Biomedical Sciences, The University of Adelaide, SA, Australia.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 11/2011; 28(3):515-30. DOI: 10.3233/JAD-2011-110533
Source: PubMed


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.

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Available from: Seyyed Hani Moussavi Nik
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    • "Zebrafish embryos and adults can be exposed to real hypoxia by depleting their water environment of oxygen or to chemical mimicry of hypoxia through, e.g., sodium azide treatment (Moussavi Nik et al., 2011). Similarly to what is observed in humans (Lukiw et al., 2001; Pluta, 2005; De Gasperi et al., 2010; Zhang and Le, 2010), hypoxia upregulates psen1, psen2, appa, appb, and bace1 in zebrafish adult brain and larvae (Moussavi Nik et al., 2012). This suggests that Aβ is produced as a protective response to hypoxia in both human and zebrafish cells – a response conserved over 450 Mya of evolutionary time. "
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