Golgi stress induces upregulation of the ER-Golgi SNARE Syntaxin-5, altered βAPP processing, and Caspase-3-dependent...

The involvement of secretory pathways and Golgi dysfunction in neuronal cells during Alzheimer's disease progression is poorly understood. Our previous overexpression and knockdown studies revealed that the intracellular protein level of Syntaxin-5, an endoplasmic reticulum-Golgi soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE), modulates beta-amyloid precursor protein processing in neuronal cells. We recently showed that changes in endogenous Syntaxin-5 protein expression occur under stress induction. Syntaxin-5 was upregulated by endoplasmic reticulum stress but was degraded by Caspase-3 during apoptosis in neuronal cells. In addition, we showed that sustained endoplasmic reticulum stress promotes Caspase-3-dependent apoptosis during the later phase of the endoplasmic reticulum stress response in NG108-15 cells. In this study, to elucidate the consequences of secretory pathway dysfunction in beta-amyloid precursor protein processing that lead to neuronal cell death, we examined the effect of various stresses on endoplasmic reticulum-Golgi SNARE expression and beta-amyloid precursor protein processing. By using compounds to disrupt Golgi function, we show that Golgi stress promotes upregulation of the endoplasmic reticulum-Golgi SNARE Syntaxin-5, and prolonged stress causes Caspase-3-dependent apoptosis. Golgi stress induced intracellular beta-amyloid precursor protein accumulation and a concomitant decrease in total amyloid-beta production. We also examined the protective effect of the chemical chaperone 4-phenylbutylate on changes in amyloid-beta production and the activation of Caspase-3 induced by endoplasmic reticulum and Golgi stress. The compound alleviated the increase in the amyloid-beta 1-42/amyloid-beta 1-40 ratio induced by endoplasmic reticulum and Golgi stress. Furthermore, 4-phenylbutylate could rescue Caspase-3-dependent apoptosis induced by prolonged organelle stress. These results suggest that organelle stress originating from the endoplasmic reticulum and Golgi has a substantial impact on the amyloidogenic processing of beta-amyloid precursor protein and Caspase-3-dependent apoptosis, leading to neuronal cell death.