Genetic and microstructural differences between gyri and sulci during gyrification in the cortical plate of fetal sheep

Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterised by decreased brain energy production (hypometabolism). Age is the main risk factor for AD but the reason for this is unclear. Brain expression of the master transcriptional regulator of hypoxia, HIF1, increases with age and hypoxia appears to coordinate many AD phenomena such as increased oxidative stress and upregulated expression of the genes involved in familial Alzheimer’s disease (fAD), leading to increased production of amyloidb peptide. PRESENILIN 1 (PSEN1) is the majority locus for mutations causing fAD and the PSEN1 protein interacts with the HIF1 component, HIF1a. Zebrafish are a versatile model organism for genetic analyses of acute hypoxic responses, so we introduced a fAD-like mutation into its psen1 gene and analysed the effects on HIF1-controlled gene expression with age. The fAD-like mutant allele appeared to accelerate brain aging in terms of changes in basal, normoxic, Hif1-responsive gene expression and an eventual shift of brains into an unexpected state where Hif1responsive genes show “inverted” expression responses to acute hypoxia. Intriguingly, these fAD-like mutant adult zebrafish also show an accelerated loss of spatial working memory with age. Our results are consistent with a view of AD as both dependent upon brain aging but manifesting as a distinct, pathological brain molecular state.