title: The BACE1-PSEN-AβPP regulatory axis has an ancient role in response to low oxygen/oxidative stress.
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.
authors: Discipline of Genetics, School of Molecular and Biomedical Sciences, The University of Adelaide, SA, Australia. seyyed.moussavinik@adelaide.edu.au
authors: Seyyed Hani
authors: SH
authors: Moussavi Nik
authors: Lachlan
authors: L
authors: Wilson
authors: Morgan
authors: M
authors: Newman
authors: Kevin
authors: K
authors: Croft
authors: Trevor A
authors: TA
authors: Mori
authors: Ian
authors: I
authors: Musgrave
authors: Michael
authors: M
authors: Lardelli
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D058893:DNA Barcoding, Taxonomic / Q000379:methods; D004625:Embryo, Nonmammalian / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D015227:Lipid Peroxidation; D008845:Microinjections; D060172:Morpholinos / Q000008:administration & dosage; D018384:Oxidative Stress / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D060172:Morpholinos; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D053763:Presenilins; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D002374:Catalase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human