ER stress response in NG108-15 cells involves upregulation of syntaxin 5 expression and reduced amyloid β peptide secretion

Abstract

Endoplasmic reticulum (ER) stress plays a role in the pathogenesis of neurodegenerative diseases such as Alzheimer׳s disease (AD). We previously showed that manipulation of the ER-Golgi-soluble N-ethylmaleimide-sensitive factor-attachment protein receptors (ER-Golgi SNARE) syntaxin 5 (Syx5) causes changes in Golgi morphology and the processing of AD-related proteins. To understand the pathophysiologic significance of these phenomena, we examined whether the expression of Syx5 is altered by ER stress. De novo synthesis of ER-Golgi SNARE Syx5 and Bet1 was induced by various ER stressors. Elevated expression of Syx5 and Bet1 was associated with increased levels of these proteins in vesicular components, including ER-Golgi-intermediate-compartment/vesicular tubular clusters. In addition, ER stress diminished amyloid β (Aβ) peptide secretion. Knockdown of Syx5 expression enhanced the secretion of Aβ peptides under condition without ER stress. Moreover, diminished Aβ peptide secretion resulting from ER stress was significantly reversed by Syx5 knockdown. These findings suggest that Syx5 plays important roles in β-amyloid precursor protein processing and in the ER stress response that precedes apoptotic cell death and may be involved in the crosstalk between these two pathways.

Keywords: Amyloid precursor protein (APP); Amyloid-beta (Aβ); Endoplasmic reticulum stress; SNARE proteins; Stress response; Syntaxin 5.