Oxidative stress in the brain at early preclinical stages of mouse scrapie

Abstract

Oxidative stress has been shown to be involved in the pathogenesis of neurodegenerative diseases including prion diseases. Although a growing body of evidence suggests direct involvement of oxidative stress in the pathogenesis of prion diseases, it is still not clear whether oxidative stress is a causative early event in these conditions or a secondary phenomenon commonly found in the progression of neurodegenerative diseases. Using a mouse scrapie model, we assessed oxidative stress in the brain at various stages of the disease progression and observed significantly increased concentration of lipid peroxidation markers, malondialdehyde and 4-hydroxyalkenals, and mRNA level of an oxidative stress response enzyme, heme oxygenase-1, at early preclinical stages of scrapie. The changes preceded dramatic synaptic loss demonstrated by immunohistochemical staining of a synaptic protein, synaptophysin. These findings imply that the brain undergoes oxidative stress even from an early stage of prion invasion into the brain. Given the well-known deleterious effects of reactive-oxygen-species-mediated damage in the brain, it is considered that the oxidative stress at the preclinical stage of prion diseases may predispose the brain to neurodegenerative mechanisms that characterize the diseases.