The Impacts of Hyperlipidemia Induced Inflammation on Brain and a Potential Treatment of Hyperlipidemic Neuronal Dysfunction by the Modulation of PERK Pathway

Date

2025-7-3

Author

Mengi Çamur, Naz

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Hyperlipidemia, a common comorbidity of obesity characterized by elevated circulating lipid levels, has been increasingly linked to neurodegeneration. However, the molecular mechanisms through which hyperlipidemia alters brain function remain poorly understood. Clarifying these mechanisms is essential for identifying therapeutic targets to prevent neuronal dysfunction before irreversible damages occur. One consequence of obesity is low-grade peripheral inflammation, which compromises blood-brain barrier (BBB) integrity. BBB disruption increases regional vulnerability to peripheral inflammatory signals and promotes local neuroinflammation, processes associated with synaptic failure and neurodegeneration. Yet, the cellular signaling pathways involved are not fully defined. A key candidate is the Protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway, a branch of the endoplasmic reticulum stress response. While transient PERK activation can restore homeostasis, chronic activation promotes inflammation and apoptosis. Evidence suggests that diet-induced hyperlipidemia activates PERK in peripheral tissues, but its role in the brain remains unclear. In this study, we investigated BBB and synaptic integrity, PERK activation, and mitochondrial stress in the hypothalamus and hippocampus of C57BL/6 and Apoe-/- mice under hyperlipidemic conditions. We further tested whether PERK inhibition via GSK2606414 or Trans-ISRIB could mitigate these effects. Our findings showed that PERK was selectively activated in the hypothalamus of Apoe-/- mice, and GSK2606414 effectively suppressed NLRP3 inflammasome signaling in this brain region.

Subject Keywords

Hyperlipidemia, PERK, Neuroinflammation, Hypothalamus, Blood-Brain Barrier

URI

https://hdl.handle.net/11511/115407

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Graduate School of Natural and Applied Sciences, Thesis