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 stabilization under hypoxia is a phenomenon conserved across vertebrate classes.

中文翻译：

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患有早老素 1 家族性阿尔茨海默病样突变的斑马鱼缺氧反应加速丧失。

衰老是阿尔茨海默病（AD）的主要危险因素，阿尔茨海默病是一种与大脑缺氧有关的疾病。大多数早发家族性 AD (EOfAD) 病例涉及PSEN1基因的显性突变。PSEN1无效突变不会导致 EOfAD。我们利用斑马鱼psen1基因中假定的亚效型和 EOfAD 样突变来探索年龄和基因型对大脑对急性缺氧反应的影响。这两种突变都会加速缺氧敏感基因表达的年龄依赖性变化，支持衰老对于 AD 的发生是必要的，但还不够。奇怪的是，年龄极大的鱼对急性缺氧的反应却相反。这与明显无法上调糖酵解有关。在人类 EOfAD 突变携带者（以及极度老化的鱼）死后大脑中，野生型PSEN1等位基因表达降低，可能与 EOfAD 发病机制有关。我们还观察到，缺氧条件下 HIF1 稳定性的年龄依赖性丧失是跨脊椎动物类别的一种保守现象。