Accelerated loss of hypoxia response and biased allele expression in zebrafish with Alzheimers disease-like mutations

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.