PUBLICATION

The BACE1-PSEN-AbetaPP Regulatory Axis has an Ancient Role in Response to Low Oxygen/Oxidative Stress

Authors
Nik, S.H., Wilson, L., Newman, M., Croft, K., Mori, T.A., Musgrave, I., and Lardelli, M.
ID
ZDB-PUB-111117-2
Date
2012
Source
Journal of Alzheimer's disease : JAD   28(3): 515-530 (Journal)
Registered Authors
Lardelli, Michael, Newman, Morgan
Keywords
Alzheimer's disease, amyloid-β protein precursor, BACE1, hypoxia, oxidative stress, presenilins, γ-secretase, zebrafish
MeSH Terms
  • Amyloid Precursor Protein Secretases/genetics
  • Amyloid Precursor Protein Secretases/metabolism*
  • Amyloid beta-Protein Precursor/genetics
  • Amyloid beta-Protein Precursor/metabolism*
  • Animals
  • Aspartic Acid Endopeptidases/genetics
  • Aspartic Acid Endopeptidases/metabolism*
  • Brain/metabolism*
  • Catalase/genetics
  • Catalase/metabolism
  • DNA Barcoding, Taxonomic/methods
  • Embryo, Nonmammalian/drug effects
  • Gene Expression Regulation, Developmental
  • Humans
  • Hypoxia/pathology*
  • Lipid Peroxidation
  • Microinjections
  • Morpholinos/administration & dosage
  • Oxidative Stress/physiology*
  • Presenilin-1/genetics
  • Presenilin-1/metabolism
  • Presenilin-2/genetics
  • Presenilin-2/metabolism
  • Presenilins/genetics
  • Presenilins/metabolism*
  • RNA, Messenger/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
22045484 Full text @ J. Alzheimers Dis.
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.
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Mapping