The molecular events that underlie prion disease neuropathology remain poorly defined. Within the hippocampus of the ME7/CV mouse scrapie model, profound CA1 neuronal loss occurs between 160 and 180 days post-infection (dpi). To elucidate the molecular events that may contribute to this neuronal loss, we have applied Affymetrix high-density oligonucleotide probe arrays to the study of ME7-infected hippocampal gene expression at 170 dpi. The study has identified 78 genes that are differentially expressed greater than 1.5-fold within the preclinical ME7-infected hippocampus prior to the profound late stage glial cell activation. The results indicate oxidative and endoplasmic reticulum (ER) stress, activated ER and mitochondrial apoptosis pathways, and activated cholesterol biosynthesis within the scrapie-infected hippocampus, and offer insight into the molecular events which underlie the neuropathology.