The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal

Abstract

Presenilin-1 (PS1) is a core component of g-secretase that is involved in neurodegeneration. We have previously shown that PS1 interacts with a mitogen-activated protein kinase [(MAPK) jun-NH2-terminal-kinase], and another MAPK (p38) is activated by ethanol withdrawal (EW), abrupt termination from chronic ethanol exposure. EW is excitotoxic in nature, induces glutamate upregulation, and provokes neuronal damage. Here, we explored a potential mechanistic pathway involving glutamate, p38 (p38a isozyme), and PS1 that may mediate EW-induced excitotoxic stress. We used the prefrontal cortex of male rats withdrawn from a chronic ethanol diet. Additionally, we used ethanol-withdrawn HT22 cells (mouse hippocampal) treated with the inhibitor of glutamate receptors [dizocilpine (MK-801)], p38aduring EW. Separately, ethanol-free HT22 cells were exposed to glutamate with or without SB203580 or DAPT. Protein levels, mRNA levels, and cell viability were assessed using immunoblotting, qualitative polymerase chain reaction, and calcein assay, respectively. The prefrontal cortex of ethanolwithdrawn rats or HT22 cells showed an increase in PS1 and p38a, which was attenuated by MK-801 and SB203580, but mimicked by glutamate treatment to ethanol-free HT22 cells. DAPT attenuated the toxic effect of EW or glutamate on HT22 cells. These results suggest that PS1 expression is triggered by glutamate through p38a, contributing to the excitotoxic stimulus of EW.

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“…Similarly, repeated ethanol exposure and removal increased p38 expression in the rat cerebellar HT22 cell line (Jung et al, 2016). Of particular interest, these experiments demonstrated augmentation of EW-induced p38 by glutamate and suppression by the NMDA receptor antagonist dizocilpine (Jung et al, 2016), indicating that glutamate activates p38 expression via NMDA receptors. These findings are concordant with a report that the prototypical receptor agonist NMDA produced neuronal apoptosis in a manner dampened by p38 inhibition (Kim et al, 2011), implicating a p38-glutamate interaction in the neuronal death.…”

“…Further, a 7 week program of daily cycles of 17 hours ethanol intoxication and 7 hours withdrawal increased p38 gene expression by 3.3-fold in rat prefrontal cortex (Rimondini et al, 2002). We demonstrated in rats that two cycles of ethanol intoxication for 4 weeks and 3 weeks EW increased p38 expression in cerebellum (Ju et al, 2012) and prefrontal cortex (Jung et al, 2016). Similarly, repeated ethanol exposure and removal increased p38 expression in the rat cerebellar HT22 cell line (Jung et al, 2016).…”

“…We demonstrated in rats that two cycles of ethanol intoxication for 4 weeks and 3 weeks EW increased p38 expression in cerebellum (Ju et al, 2012) and prefrontal cortex (Jung et al, 2016). Similarly, repeated ethanol exposure and removal increased p38 expression in the rat cerebellar HT22 cell line (Jung et al, 2016). Of particular interest, these experiments demonstrated augmentation of EW-induced p38 by glutamate and suppression by the NMDA receptor antagonist dizocilpine (Jung et al, 2016), indicating that glutamate activates p38 expression via NMDA receptors.…”

“…Recently, we demonstrated elevated PS1 expression in brains of young adult rats after repeated EW (Jung et al, 2016). Also, high dose glutamate induced PS1 over-expression in HT22 neuronal cells, placing PS1 in the molecular network associated with excitotoxicity.…”

“…Preclinical studies by the authors demonstrated the association between repeated EW and brain aging. Rats undergoing repeated EW showed earlier motoric impairment than their ethanol-free counterparts (Jung et al, 2011), and increased activity of presenilin-1 (PS1), an enzyme that generates AD’s pathological hallmark, amyloid β (Aβ) (Jung et al, 2016). Indeed, Aβ accumulated in the rat prefrontal cortex after repeated EW (Ryou et al, 2017).…”