PT  - JOURNAL ARTICLE
AU  - Morgan Newman
AU  - Hani Moussavi Nik
AU  - Greg T. Sutherland
AU  - Woojin S. Kim
AU  - Glenda M. Halliday
AU  - Suman Jayadev
AU  - Carole Smith
AU  - Thaksaon Kittipassorn
AU  - Dan J. Peet
AU  - Michael Lardelli
TI  - Accelerated loss of hypoxia response and biased allele expression in zebrafish with Alzheimer’s disease-like mutations
AID  - 10.1101/526277
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 526277
4099  - http://biorxiv.org/content/early/2019/01/21/526277.short
4100  - http://biorxiv.org/content/early/2019/01/21/526277.full
AB  - Ageing is the major risk factor for Alzheimer’s disease (AD), a condition involving brain hypoxia. Expression of transcriptional regulator of cellular responses to hypoxia, HYPOXIA-INDUCIBLE FACTOR-1 (HIF1), increases with brain age. HIF1 interacts with PRESENILIN 1 (PSEN1), the major locus for mutations causing familial AD (fAD). We introduced two fAD-like mutations into zebrafish psen1 and analysed their effects on HIF1-controlled gene expression in brains. Mutant psen1 alleles accelerated age-dependent changes in HIF1-controlled gene expression. Also, aged brains shifted into an unexpected state where HIF1-controlled genes show “inverted” responses to hypoxia. Intriguingly, zebrafish psen1 expression was biased towards mutant psen1 alleles over wild type alleles in an age- and hypoxia-dependent manner. Brains of human PSEN1 fAD mutation carriers showed reduced PSEN1 mRNA expression but no allelic bias. Our results are consistent with “molecular ageing” being a necessary precondition for AD and with AD identifiable as a distinct, pathological brain molecular state.