The Zebrafish Equivalent of Alzheimer’s Disease-Associated PRESENILIN Isoform PS2V Regulates Inflammatory and Other Responses to Hypoxic Stress

Article type: Research Article

Authors: Ebrahimie, Esmaeil^{a; b; c; 1; *} | Moussavi Nik, Seyyed Hani^{a; 1} | Newman, Morgan^{a; 1} | Van Der Hoek, Mark^d | Lardelli, Michael^{a; *}

Affiliations: [a] Department of Genetics and Evolution, School of Biological Sciences, University of Adelaide, Adelaide, Australia | [b] School of Information Technology and Mathematical Sciences, Division of Information Technology, Engineering and the Environment, University of South Australia, Adelaide, Australia | [c] School of Biological Sciences, Faculty of Science and Engineering, Flinders University, Adelaide, Australia | [d] Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, Australia

Correspondence: [*] Correspondence to: Dr. Esmaeil Ebrahimie Department of Genetics and Evolution, School of Biological Sciences, The University of Adelaide, SA 5005, Australia. Tel.: +61 8 8312522; Fax: +61 8 83134362; E-mail: [email protected] (Dr. E. Ebrahimie);

Correspondence: [*] Correspondence to: Dr. Michael Lardelli, Department of Genetics and Evolution, School of Biological Sciences, The University of Adelaide, SA 5005, Australia. Tel.: +61 8 83133212; Fax: +61 8 83134362; E-mail: [email protected] (Dr. M. Lardelli).

Note: [1] These authors contributed equally to this work.

Abstract: Dominant mutations in the PRESENILIN genes PSEN1 and PSEN2 cause familial Alzheimer’s disease (fAD) that usually shows onset before 65 years of age. In contrast, genetic variation at the PSEN1 and PSEN2 loci does not appear to contribute to risk for the sporadic, late onset form of the disease (sAD), leading to doubts that these genes play a role in the majority of AD cases. However, a truncated isoform of PSEN2, PS2V, is upregulated in sAD brains and is induced by hypoxia and high cholesterol intake. PS2V can increase γ-secretase activity and suppress the unfolded protein response (UPR), but detailed analysis of its function has been hindered by lack of a suitable, genetically manipulable animal model since mice and rats lack this PRESENILIN isoform. We recently showed that zebrafish possess an isoform, PS1IV, that is cognate to human PS2V. Using an antisense morpholino oligonucleotide, we can block specifically the induction of PS1IV that normally occurs under hypoxia. Here, we exploit this ability to identify gene regulatory networks that are modulated by PS1IV. When PS1IV is absent under hypoxia-like conditions, we observe changes in expression of genes controlling inflammation (particularly sAD-associated IL1B and CCR5), vascular development, the UPR, protein synthesis, calcium homeostasis, catecholamine biosynthesis, TOR signaling, and cell proliferation. Our results imply an important role for PS2V in sAD as a component of a pathological mechanism that includes hypoxia/oxidative stress and support investigation of the role of PS2V in other diseases, including schizophrenia, when these are implicated in the pathology.

Keywords: Gene regulatory networks, neurodegenerative diseases, transcriptome profiling, zebrafish

DOI: 10.3233/JAD-150678

Journal: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 581-608, 2016