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Accelerated loss of hypoxia response and biased allele expression in zebrafish with Alzheimers disease-like mutations
- Authors :
- Newman, Morgan
Moussavi Nik, Hani
Sutherland, Greg
Kim, Woojin
Halliday, Glenda
Jayadev, Suman
Smith, Carole
Kittipassorn, Thaksaon
Peet, Dan
Lardelli, Michael - Publication Year :
- 2019
- Publisher :
- Cold Spring Harbor Laboratory, 2019.
-
Abstract
- Ageing is the major risk factor for Alzheimers 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.
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.sharebioRxiv..291308128a7cdc273fff1bd31bfbc5f0
- Full Text :
- https://doi.org/10.1101/526277