A zebrafish model of familial Alzheimer's disease (fAD) shows dramatic, early changes in behaviour and gene expression and a predisposition to pathological change

M Newman1, E Ebrahimie1, SH Moussavi Nik1, S Jayadev2, T Jayne1, X-F Zhou3 and M Lardelli1

  1. Centre for Molecular Pathology, University of Adelaide, SA 5005 Australia
  2. Department of Neurology, University of Washington, Seattle, Washington 98195, USA
  3. School of Pharmacy and Medical Sciences, University of South Australia, SA 5000, Australia

Alzheimer's disease (AD) develops over decades but the early, initiating pathological stresses are undefined. We report the first detailed molecular analysis of young adult, pre-AD histopathology brains from a heterozygous, endogenous fAD PRESENILIN (PSEN) mutation model (i.e. closely modeling the human fAD genetic state rather than attempting to phenocopy late-stage AD pathology). fAD mutation K115Efs truncates the coding sequence of PSEN2 to resemble the hypoxia- and cholesterol-inducible PSEN2 isoform PS2V. We modeled this mutation in zebrafish (K97Gfs in psen1). Heterozygous K97Gfs brains show a reduced unfolded protein response (UPR) despite the existence of a brain-specific homeostatic mechanism that upregulates transcripts from the non-mutant allele to maintain normal gene expression. Large, highly statistically significant differences are observed between the brain transcriptomes/proteomes of young adult heterozygous fAD-like mutant and non-mutant fish. Changes in behaviour and gene expression are observable in very young heterozygous mutant zebrafish larvae (facilitating future exploitation in unbiased drug screens). Systems biology analyses indicate that RNA/protein expression changes driven by the mutation might make the brain more susceptible to initiation of neuroinflammatory, metabolic and phosphorylation-state responses that would then be self-reinforcing. Our results support a model of early onset fAD whereby PSEN fAD mutations force changes in cellular state that prematurely occupy a proportion of cells' homeostatic capacity thereby lowering the threshold at which that homeostatic capacity is overwhelmed by cellular stressors such as hypoxia. Self-reinforcing pathological loops then drive the brain into a neurodegenerative state.