PERK inhibition mitigates acrylamide-induced tau phosphorylation and synaptic deficits via the GSK-3β and ATF4 pathways in human neuroblastoma SH-SY5Y cells.

Acrylamide (ACR), a potential neurotoxin prevalent in carbohydrate-rich foods, poses a significant public health concern. While ACR exposure is known to induce tau phosphorylation and synaptic impairment, the underlying mechanisms remain incompletely understood. The aberrant activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor-2α (eIF2α) signaling pathway is emerging as a major common theme in neurodegenerative disorders. This study investigated the role of the PERK-eIF2α signaling pathway in ACR-induced neurotoxicity using human neuroblastoma SH-SY5Y cells. Our results showed that ACR exposure not only significantly increased tau phosphorylation at specific epitopes (Ser262 and Ser202/Thr205) but also markedly reduced the levels of key synaptic proteins, including phosphorylated cAMP response element-binding protein (P-CREB), brain derived neurotrophic factor (BDNF), Synapsin-1, and Synaptophysin. Concurrently, ACR activated the PERK-eIF2α branch of the unfolded protein response. Crucially, pharmacological inhibition of PERK by GSK2606414 attenuated ACR-induced tau phosphorylation by restoring the inhibitory phosphorylation of glycogen synthase kinase-3β (Ser9). The same treatment also reversed the reductions in P-CREB and BDNF, likely through downregulation of the transcription factor 4. However, the PERK inhibitor failed to rescue the decreased expression of Synapsin-1 and Synaptophysin. These findings demonstrate that the PERK-eIF2α pathway is a key mediator in ACR-induced tau phosphorylation and P-CREB/BDNF impairment, but not in the loss of synaptic vesicle proteins. Our study thus reveals a dual-mechanism for ACR neurotoxicity and suggests that targeting the PERK-eIF2α axis could offer a promising strategy for mitigating specific pathological features.