Accelerated brain aging towards transcriptional inversion in a zebrafish model of the K115fs mutation of human PSEN2

Abstract

BackgroundThe molecular changes involved in Alzheimer's disease (AD) progression remain unclear since we cannot easily access antemortem human brains. Some non-mammalian vertebrates such as the zebrafish preserve AD-relevant transcript isoforms of the PRESENILIN genes lost from mice and rats. One example is PS2V, the alternative transcript isoform of the PSEN2 gene. PS2V is induced by hypoxia/oxidative stress and shows increased expression in late onset, sporadic AD brains. A unique, early onset familial AD mutation of PSEN2, K115fs, mimics the PS2V coding sequence suggesting that forced, early expression of PS2V-like isoforms may contribute to AD pathogenesis. Here we use zebrafish to model the K115fs mutation to investigate the effects of forced PS2V-like expression on the transcriptomes of young adult and aged adult brains. MethodsWe edited the zebrafish genome to model the K115fs mutation. To explore its effects at the molecular level, we analysed the brain transcriptome and proteome of young (6-month-old) and aged (24-month-old) wild type and heterozygous mutant female sibling zebrafish. Finally, we used gene co-expression network analysis (WGCNA) to compare molecular changes in the brains of these fish to human AD. ResultsYoung heterozygous mutant fish show transcriptional changes suggesting accelerated brain aging and increased glucocorticoid signalling. These early changes precede a

Comparative analysis of Alzheimer’s disease knock-in model brain transcriptomes implies changes to energy metabolism as a causative pathogenic stress

“…We first collated our findings from our zebrafish models of EOfAD-like mutations in psen1 (Barthelson et al, 2021; Hin et al, 2020a; Hin et al, 2020b; Newman et al, 2019), psen2 (Barthelson et al, 2020c) and sorl1 (Barthelson et al, 2020b; Barthelson et al, 2020e). An advantage of using zebrafish for RNA-seq analyses is minimisation of genetic and environmental noise through breeding strategies such as that shown in Figure 1A .…”

“…K97fs is a frameshift mutation and so does not follow the “reading-frame preservation rule” (Jayne et al, 2016) of presenilin EOfAD mutations. However, K97fs (Hin et al, 2020a) models the PS2V isoform of human PSEN2 (Sato et al, 1999), that shows increased expression in LOAD brains (see (Moussavi Nik et al, 2015) for an explanation) and so is still an AD-relevant mutation. Genes encoding the components of ribosomal subunits, as defined by the gene set KEGG_RIBOSOME , were affected by all the EOfAD-like mutations but also by non-EOfAD-like mutations in psen1 and psen2 ( Figure 1D ).…”

“…Our group has exploited the zebrafish to generate a collection of knock-in models of EOfAD-like mutations in order to analyse their young brain transcriptomes (Barthelson et al, 2021; Barthelson et al, 2020b; Barthelson et al, 2020c; Barthelson et al, 2020e; Hin et al, 2020a; Hin et al, 2020b; Jiang et al, 2020; Newman et al, 2019). Our experimental philosophy has been to replicate, as closely as possible, the single heterozygous mutation state of EOfAD in humans, thereby avoiding possibly misleading assumptions regarding the molecular mechanism(s) underlying the disease.…”

PRESENILIN 1mutations causing early-onset familial Alzheimer’s disease or familial acne inversa differ in their effects on genes facilitating energy metabolism and signal transduction

“…due to environmental and genotypic variation) (K. Barthelson, unpublished results). In contrast, zebrafish brain transcriptomes show only subtle influences of sex, and very large numbers of siblings can be generated from single mating event, alleviating potential litter-of-origin issues [39][40][41][42][43]. In 2014, our laboratory began a program of creating knock-in models of EOfAD-like (and non-EOfAD-like) mutations in the zebrafish genes orthologous to PSEN1, PSEN2, and SORL1.…”

No observed effect on brain vasculature of Alzheimer’s disease-related mutations in the zebrafish presenilin 1 gene

“…Mutations allowing production of a transcript(s) with an altered coding sequence but, nevertheless, utilising the original stop codon cause EOfAD while mutant alleles coding only for truncated proteins do not. We previously generated knock-in models in zebrafish with each of these types of mutant psen1 allele: K97Gfs, a frameshift mutation encoding a truncated protein similar to the human PS2V isoform that is increased in sporadic, late onset AD [ 6 ], and Q96_K97del: an EOfAD-like, reading-frame-preserving deletion of two codons [ 7 ].…”