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Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease

View ORCID ProfileNhi Hin, View ORCID ProfileMorgan Newman, View ORCID ProfileJan Kaslin, Alon M. Douek, View ORCID ProfileAmanda Lumsden, View ORCID ProfileXin-Fu Zhou, Alastair Ludington, View ORCID ProfileDavid L. Adelson, View ORCID ProfileStephen Pederson, View ORCID ProfileMichael Lardelli
doi: https://doi.org/10.1101/262162
Nhi Hin
#Joint first authors
1University of Adelaide, School of Biological Sciences, Bioinformatics Hub, Adelaide, SA, Australia
2University of Adelaide, School of Biological Sciences, Centre for Molecular Pathology, Alzheimer’s Disease Genetics Laboratory, Adelaide, SA, Australia
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Morgan Newman
#Joint first authors
2University of Adelaide, School of Biological Sciences, Centre for Molecular Pathology, Alzheimer’s Disease Genetics Laboratory, Adelaide, SA, Australia
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Jan Kaslin
3Monash University, Australian Regenerative Medicine Institute, Clayton, Victoria, Australia
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Alon M. Douek
3Monash University, Australian Regenerative Medicine Institute, Clayton, Victoria, Australia
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Amanda Lumsden
4Flinders University, College of Medicine and Public Health, and Centre for Neuroscience, Adelaide, SA
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Xin-Fu Zhou
5University of South Australia, School of Pharmacy and Medical Sciences, Adelaide, SA, Australia
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Alastair Ludington
1University of Adelaide, School of Biological Sciences, Bioinformatics Hub, Adelaide, SA, Australia
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David L. Adelson
6University of Adelaide, School of Biological Sciences, Centre for Bioinformatics and Computational Genetics, Adelaide, SA, Australia
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Stephen Pederson
*Joint senior authors
^Corresponding author for bioinformatics
1University of Adelaide, School of Biological Sciences, Bioinformatics Hub, Adelaide, SA, Australia
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Michael Lardelli
*Joint senior authors
+Corresponding author for Alzheimer’s disease and zebrafish biology
2University of Adelaide, School of Biological Sciences, Centre for Molecular Pathology, Alzheimer’s Disease Genetics Laboratory, Adelaide, SA, Australia
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Abstract

Alzheimer’s disease (AD) develops silently over decades. We cannot easily access and analyse pre-symptomatic brains, so the earliest molecular changes that initiate AD remain unclear. Previously, we demonstrated that the genes mutated in early-onset, dominantly-inherited familial forms of AD (fAD) are evolving particularly rapidly in mice and rats. Fortunately, some non-mammalian vertebrates such as the zebrafish preserve fAD-relevant transcript isoforms of the PRESENILIN (PSEN1 and PSEN2) genes that these rodents have lost. Zebrafish are powerful vertebrate genetic models for many human diseases, but no genetic model of fAD in zebrafish currently exists. We edited the zebrafish genome to model the unique, protein-truncating fAD mutation of human PSEN2, K115fs. Analysing the brain transcriptome and proteome of young (6-month-old) and aged, infertile (24-month-old) wild type and heterozygous fAD-like mutant female sibling zebrafish supports accelerated brain aging and increased glucocorticoid signalling in young fAD-like fish, leading to a transcriptional ‘inversion’ into glucocorticoid resistance and vast changes in biological pathways in aged, infertile fAD-like fish. Notably, one of these changes involving microglia-associated immune responses regulated by the ETS transcription factor family is preserved between our zebrafish fAD model and human early-onset AD. Importantly, these changes occur before obvious histopathology and likely in the absence of Aβ. Our results support the contributions of early metabolic and oxidative stresses to immune and stress responses favouring AD pathogenesis and highlight the value of our fAD-like zebrafish genetic model for elucidating early changes in the brain that promote AD pathogenesis. The success of our approach has important implications for future modelling of AD.

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Posted February 20, 2018.
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Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease
Nhi Hin, Morgan Newman, Jan Kaslin, Alon M. Douek, Amanda Lumsden, Xin-Fu Zhou, Alastair Ludington, David L. Adelson, Stephen Pederson, Michael Lardelli
bioRxiv 262162; doi: https://doi.org/10.1101/262162
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Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease
Nhi Hin, Morgan Newman, Jan Kaslin, Alon M. Douek, Amanda Lumsden, Xin-Fu Zhou, Alastair Ludington, David L. Adelson, Stephen Pederson, Michael Lardelli
bioRxiv 262162; doi: https://doi.org/10.1101/262162

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