Increased Levels of Nrf-2/ HO-1 in the Early Pathogenesis of Alzheimer's Disease

Introduction Alzheimer’s disease (AD) is characterised by the presence of plaques, tangles and neuronal loss. At autopsy, the superior temporal gyrus (STG) of AD cases contains plaques, but few tangles and moderate neuronal loss. Therefore, the STG may represent an early-stage in AD pathogenesis or possibly be an area in the AD brain resistant to disease progression. We previously reported evidence suggestive of accumulating H 2 O 2 in our AD cohort. The brains high lipid content makes it particularly susceptible to lipid peroxidation, therefore we aimed to explore a role for the Nrf-2/ heme oxygenase-1 (HO-1) antioxidant response system in the early stages of AD progression. Method Samples included human brain tissue from age, gender and APOE e4-matched AD cases (n=20) and controls (n=20). Gene regulation was assessed with Quantitative-PCR and related to protein levels (ELISAs and Western Blotting) and corresponding activity (where appropriate) in STG homogenates. Oxidative damage was judged by 4-hydroxynonenal (4-HNE) immunoreactivity, where required caspase 3/7 activity was assessed as a marker of apoptosis. Results Nrf-2 and HO-1 mRNA increased (p Discussion No significant difference in cell viability was observed in the AD STG and extents of lipid (per)oxidation were unchanged. Together, these results suggest possible resistance of the STG to further AD pathology; possibly due to activation of the Nrf-HO-1 system in response to accumulating H 2 O 2 via the activation of the p-ERK signaling pathway. These data suggest that HO inducers may be a potential therapy for early stage AD.