Assessment of the impacts of hyperlipidemia on brain and modulation of perk pathway against hyperlipidemia- induced synaptic impairment on hippocampus

Date

2019

Author

Aşkın, Bilge

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Hyperlipidemia is characterized by elevated total cholesterol levels in the circulation, and it is often associated with co-occurrence of neuronal dysfunction and subsequent neurodegeneration. Hyperlipidemia-induced inflammation, synaptic damage and neuronal loss in hippocampus as well as in other regions of the brain consequently leads to cognitive decline. Due to its role in protein translation and cell fate determination, PKR-like endoplasmic reticulum kinase (PERK) arm of the Endoplasmic Reticulum (ER) stress is likely to be involved in hyperlipidemia-induced neurodegeneration. Therefore, attenuation of PERK pathway would provide a neuroprotective effect against the negative effects of hyperlipidemia. The first half of the study was aimed to examine hyperlipidemia-induced inflammatory and synaptic changes in the cortex and hippocampus and the involvement of PERK pathway in hyperlipidemia-induced changes. The second half of the study was aimed to assess the impacts of PERK pathway modulation using Sephin1 on hyperlipidemia-induced synaptic impairment in hippocampus. Our results showed that hyperlipidemia elevated the stress status of the cortex and potentially impaired synaptic integrity by decreasing synaptic protein levels. In the cortex, decreased synaptic protein levels coincided with elevated astrogliosis and pro- inflammatory cytokine levels. Unlike cortex, hippocampus was not affected by the early effects of hyperlipidemia even though astrogliosis level was markedly increased. Increased astrogliosis may provide a neuroprotective activity against the early effects of hyperlipidemia in hippocampus due to its privileged involvement in neurogenesis. Sephin1 was not an effective therapeutic approach to prevent hyperlipidemia-induced synaptic protein loss seen in hippocampus since stress response was not yet triggered in hippocampus.

Subject Keywords

Hippocampus (Brain), Hyperlipidemia, Hippocampus, ER Stress, PERK.

URI

http://etd.lib.metu.edu.tr/upload/12623521/index.pdf
https://hdl.handle.net/11511/43799

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Graduate School of Natural and Applied Sciences, Thesis