Accelerated loss of hypoxia response in zebrafish with familial Alzheimer's disease-like mutation of Presenilin 1

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dc.contributor.authorNewman, M.
dc.contributor.authorMoussavi Nik, S.H.
dc.contributor.authorSutherland, G.T.
dc.contributor.authorHin, N.
dc.contributor.authorKim, W.S.
dc.contributor.authorHalliday, G.M.
dc.contributor.authorJayadev, S.
dc.contributor.authorSmith, C.
dc.contributor.authorLaird, A.
dc.contributor.authorLucas, C.
dc.contributor.authorKittipassorn, T.
dc.contributor.authorPeet, D.J.
dc.contributor.authorLardelli, M.
dc.date.issued2020
dc.description.abstractAgeing 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.
dc.description.statementofresponsibilityMorgan Newman, Hani Moussavi Nik, Greg T Sutherland, Nhi Hin, Woojin S Kim, Glenda M Halliday ... et al.
dc.identifier.citationHuman Molecular Genetics, 2020; 29(14):2379-2394
dc.identifier.doi10.1093/hmg/ddaa119
dc.identifier.issn0964-6906
dc.identifier.issn1460-2083
dc.identifier.orcidNewman, M. [0000-0002-4930-4529]
dc.identifier.orcidMoussavi Nik, S.H. [0000-0002-5727-6863]
dc.identifier.orcidHin, N. [0000-0003-3063-4058]
dc.identifier.orcidKittipassorn, T. [0000-0001-9854-2905]
dc.identifier.orcidPeet, D.J. [0000-0002-6085-8936]
dc.identifier.orcidLardelli, M. [0000-0002-4289-444X]
dc.identifier.urihttp://hdl.handle.net/2440/129497
dc.language.isoen
dc.publisherOxford University Press (OUP)
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1126422
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1079679
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1037746
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1095127
dc.rights© The Author(s) 2020. Published by Oxford University Press. All rights reserved.
dc.source.urihttps://doi.org/10.1093/hmg/ddaa119
dc.subjectaging; alzheimer's disease; mutation; hypoxia; zebrafish; brain; psen1 gene
dc.titleAccelerated loss of hypoxia response in zebrafish with familial Alzheimer's disease-like mutation of Presenilin 1
dc.typeJournal article
pubs.publication-statusPublished

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