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


Autoři: Nhi Hin aff001;  Morgan Newman aff002;  Jan Kaslin aff003;  Alon M. Douek aff003;  Amanda Lumsden aff004;  Seyed Hani Moussavi Nik aff001;  Yang Dong aff001;  Xin-Fu Zhou aff005;  Noralyn B. Mañucat-Tan aff005;  Alastair Ludington aff001;  David L. Adelson aff006;  Stephen Pederson aff001;  Michael Lardelli aff002
Působiště autorů: Bioinformatics Hub, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia aff001;  Alzheimer’s Disease Genetics Laboratory, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia aff002;  Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia aff003;  College of Medicine and Public Health, and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia aff004;  School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia aff005;  Centre for Bioinformatics and Computational Genetics, School of Bioogical Sciences, Adelaide, South Australia, Australia aff006
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227258

Souhrn

Background

The 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.

Methods

We 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.

Results

Young heterozygous mutant fish show transcriptional changes suggesting accelerated brain aging and increased glucocorticoid signalling. These early changes precede a transcriptional ‘inversion’ that leads to glucocorticoid resistance and other likely pathological changes in aged heterozygous mutant fish. Notably, microglia-associated immune responses regulated by the ETS transcription factor family are altered in both our zebrafish mutant model and in human AD. The molecular changes we observe in aged heterozygous mutant fish occur without obvious histopathology and possibly in the absence of Aβ.

Conclusions

Our results suggest that forced expression of a PS2V-like isoform contributes to immune and stress responses favouring AD pathogenesis. This highlights the value of our zebrafish genetic model for exploring molecular mechanisms involved in AD pathogenesis.

Klíčová slova:

Alzheimer's disease – Gene expression – Genetic networks – Immune response – Mutation – Neural networks – Polymerase chain reaction – Zebrafish


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2020 Číslo 1