Investigating hyperlipidemia-driven organelle stress and neuroinflammation on the mouse cerebral cortex: insights into the intervention of perk pathway

Abstract

Deficits in the metabolism of lipids called hyperlipidemia have been linked to a higher risk of developing neurodegenerative diseases. Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) signaling is crucial in cellular homeostasis. Abnormalities in the PERK have been associated with neurodegeneration. Mitophagy and the PERK pathway emphasize how cellular stress responses are regulated to preserve cellular homeostasis and mitochondrial quality control. The activity of main mitophagy regulators, such as Parkin and PINK1 (PTEN-induced kinase 1), is regulated by the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) by PERK. If lipid metabolism is at a high level, abnormalities in the mitochondria and endoplasmic stress (ER) emerge. During the ER stress activation, the PERK pathway is induced, and mitophagy is blocked, causing an enhancement in the neuroinflammation. The underlying molecular mechanism by which hyperlipidemia impacts the PERK pathway and mitophagy in the cerebral cortex, as well as the relationship between mitophagy and neuroinflammation, is not fully understood. In this study, Apoe-/- and C57BL/6 mice were given a chow or western diet to stimulate hyperlipidemia. Moreover, western diet-fed Apoe-/- mice were injected with PERK inhibitors, GSK2606414 and Trans-ISRIB, intraperitoneally for six weeks to suppress the PERK pathway. This study explores the effects of hyperlipidemia on the PERK pathway, inflammatory and mitophagy markers in the cerebral cortex of chow and western diet-fed C57BL/6 and Apoe-/- mice and investigates whether the inhibition of the PERK pathway can change the levels of inflammatory and mitochondrial markers in the cerebral cortex of hyperlipidemic mice subjects. mRNA and protein expression levels of mitophagy and inflammatory markers were assessed using the RT-qPCR and western blot, respectively. PERK pathway activation under hyperlipidemia conditions was not determined. Nevertheless, significant alterations in mitophagy markers and inflammation were detected in Apoe-/- mice apart from the diet. Furthermore, significant alterations were not seen in the PERK pathway markers; however, mitophagy was stimulated, and some inflammation markers were significantly decreased mildly at the cortical tissue of WD-fed Apoe-/- mice administrated with PERK pathway inhibitors, GSK2606414 and Trans-ISRIB. Besides, no statistically significant changes were observed in the transcript levels of the inflammatory markers. Taken together, hyperlipidemia did not cause the PERK pathway to be activated in the cerebral cortex of mice; nevertheless, it mildly altered inflammation and caused mild effects of the dysregulation of the mitochondria by hyperlipidemia independent from the PERK pathway. Furthermore, although the PERK pathway was not inhibited by the administration of PERK pathway inhibitors, mitophagy was induced, and inflammation was decreased mildly. Targeting the PERK pathway with GSK2606414 and Trans-ISRIB inhibitors from the cerebral cortex would not be a therapeutic approach for neurodegenerative diseases.