Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of γ-secretase activity

Abstract

The PRESENILIN1 and PRESENILIN2 genes encode structurally related proteases essential for γ-secretase activity. Of nearly 200 PRESENILIN mutations causing early onset, familial Alzheimer's disease (FAD) only the K115Efx10 mutation of PSEN2 causes truncation of the open reading frame. If translated, the truncated product would resemble a naturally occurring isoform of PSEN2 named PS2V that is induced by hypoxia and found at elevated levels in late onset Alzheimer's disease (AD) brains. The function of PS2V is largely unexplored. We show that zebrafish possess a PS2V-like isoform, PS1IV, produced from the fish's PSEN1 rather than PSEN2 orthologous gene. The molecular mechanism controlling formation of PS2V/PS1IV was probably present in the ancient common ancestor of the PSEN1 and PSEN2 genes. Human PS2V and zebrafish PS1IV have highly divergent structures but conserved abilities to stimulate γ-secretase activity and to suppress the unfolded protein response (UPR) under hypoxia. The putative protein truncation caused by K115Efx10 resembles PS2V in its ability to increase γ-secretase activity and suppress the UPR. This supports increased Aβ levels as a common link between K115Efx10 early onset AD and sporadic, late onset AD. The ability of mutant variants of PS2V to stimulate γ-secretase activity partially correlates with their ability to suppress the UPR. The cytosolic, transmembrane and luminal domains of PS2V are all critical to its γ-secretase and UPR-suppression activities. Our data support a model in which chronic hypoxia in aged brains promotes excessive Notch signalling and accumulation of Aβ that contribute to AD pathogenesis.

Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease

“…Moussavi Nik et al . () observed that the zebrafish truncated ortholog of PS2V could suppress the UPR response in zebrafish, as described in human neuronal cells. Recently, Ebrahimie et al .…”

“…Recently, Moussavi Nik et al . () reported that both the human PS2V and the zebrafish ortholog, PS1IV, stimulated the activity of γ‐secretase and APP cleavage. Moreover, the hmga1 gene, an ortholog to human HMGA1A , is also a hypoxia‐inducible gene in the zebrafish genome provoking an alternative splicing of the presenilin gene product (Moussavi Nik et al .…”

Accelerated loss of hypoxia response in zebrafish with familial Alzheimer’s disease-like mutation of Presenilin 1

“…However, in the K97fs mutation heterozygotes, there is an increase in mutant transcript levels with age and under stress despite that this allele's open reading frame is truncated. Since the PSEN genes are involved in regulating the unfolded protein response [27,31,68], (a stress response that includes regulation of mRNA stability [69,70]), it is conceivable that the allele-specific changes in psen1 mRNA level reflect changes in RNA stability rather than changes in the rate of transcription initiation. It may be possible to distinguish between these two mechanisms by comparison of changes in mRNA versus nascent transcript levels using PCRs specific for spliced and un-spliced transcripts [67].…”

“…Therefore, we tested the effect of acute hypoxia on the bias in allele expression in young and aged adult zebrafish brains. Gene expression responses to hypoxia can be induced by exposure of zebrafish to oxygen-depleted water for ~2.5 hours (oxygen concentration of 6.6  0.5 mg/L in normoxia and 1.1  0.5mg/L in hypoxia [23,31]).…”

Mitochondrion to endoplasmic reticulum apposition length in zebrafish embryo spinal progenitors is unchanged in response to perturbations associated with Alzheimer’s disease

“…Exposure of larvae to sodium azide (NaN 3 , Sigma-Aldrich CHEMIE GmbH, Steinheim, Germany) was performed at 100μM that we have previously demonstrated is an effective concentration for mimicry of hypoxia [58, 59]. NaN 3 was added to the aqueous support medium of 36 hpf embryos until they developed to 48 hpf.…”