Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/129497
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Type: Journal article
Title: Accelerated loss of hypoxia response in zebrafish with familial Alzheimer's disease-like mutation of Presenilin 1
Author: Newman, M.
Nik, H.M.
Sutherland, G.T.
Hin, N.
Kim, W.S.
Halliday, G.M.
Jayadev, S.
Smith, C.
Laird, A.
Lucas, C.
Kittipassorn, T.
Peet, D.J.
Lardelli, M.
Citation: Human Molecular Genetics, 2020; 29(14):2379-2394
Publisher: Oxford University Press (OUP)
Issue Date: 2020
ISSN: 0964-6906
1460-2083
Statement of
Responsibility: 
Morgan Newman, Hani Moussavi Nik, Greg T Sutherland, Nhi Hin, Woojin S Kim, Glenda M Halliday ... et al.
Abstract: Ageing is the major risk factor for Alzheimer's disease (ad), a condition involving brain hypoxia. The majority of early onset familial ad (EOfAD) cases involve dominant mutations in the gene PSEN1. PSEN1 null mutations do not cause EOfAD. We exploited putative hypomorphic and EOfAD-like mutations in the zebrafish psen1 gene to explore the effects of age and genotype on brain responses to acute hypoxia. Both mutations accelerate age-dependent changes in hypoxia-sensitive gene expression supporting that ageing is necessary, but insufficient, for ad occurrence. Curiously, the responses to acute hypoxia become inverted in extremely aged fish. This is associated with an apparent inability to upregulate glycolysis. Wild type PSEN1 allele expression is reduced in post-mortem brains of human EOfAD mutation carriers (and extremely aged fish), possibly contributing to EOfad pathogenesis. We also observed that age-dependent loss of HIF1 stabilisation under hypoxia is a phenomenon conserved across vertebrate classes.
Keywords: aging; alzheimer's disease; mutation; hypoxia; zebrafish; brain; psen1 gene
Rights: © The Author(s) 2020. Published by Oxford University Press. All rights reserved.
RMID: 1000022647
DOI: 10.1093/hmg/ddaa119
Grant ID: http://purl.org/au-research/grants/nhmrc/1126422
http://purl.org/au-research/grants/nhmrc/1079679
http://purl.org/au-research/grants/nhmrc/1037746
http://purl.org/au-research/grants/nhmrc/1095127
Appears in Collections:Biochemistry publications

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