Consuming high fat diet for long periods of time increases neuroinflammation, which may result in cognitive decline and loss in memory formation. Excessive free fatty acid influx stresses the ER and mitochondria, two important organelles taking part in protein folding and energy production. The ER responds to stress in part by activating Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) pathway. It has been shown that PERK pathway activation inhibits mitophagy (autophagy of mitochondria) in macrophages. Since microglia are the immune cells of the Central Nervous System (CNS), first I investigated the effects of high fat diet in the cortex of wild type (C57BL/6) and ApoE -/- mice by looking at microglial marker Iba1. Western Blot analysis showed no significant effects of diet and genotype on Iba1 level. I also found that there is no correlation between Iba1 and GFAP (astrocyte marker) levels for these mice. Brain contains many other types of cells and in order to effects of ER stress directly on the microglia, I moved on to the BV2 mouse microglial cell line. There were differential effects of ER stress induction with thapsigargin and palmitate treatments. An increase in ER stress markers such as CHOP and p-IRE1 has been observed with both treatments. While CHOP protein levels could not reach significance, there was an increasing numerical trend. p-IRE1 was marginally significant for both treatments (p=0.087 for thapsigargin and p=0.061 for 100 M palmitate). Mitophagy indicators (Pink1 and p62) were assessed with Western Blot analysis after successful mitochondria isolation from BV2 cells. The data indicated that p62 marginally increased with both palmitate (p=0.61) and thapsigargin (p=0.1) treatments. Following both treatments, very subtle effects of ER stress were observed. This suggests that further experiments examining optimal dosage and duration need to be performed. Overall, the induction of ER stress appears to induce mitophagy and alter microglia, which likely leads to altered cellular and synaptic function.