Genetic knockout of estrogen receptor-ïβ¢ contributes to Alzheimer's disease pathogenesis by impairing mitochondrial function in females

Abstract

immunoprecipitates. Results: We analyzed the cortical proteome of the APP23 mouse model, at presymptomatic (1 month) and symptomatic age (7 months). At presymptomatic age, proteins related to glycolysis were predominantly altered according to enrichment analysis. At symptomatic age, proteins related to oxidative phosphorylation were enriched. In addition to changes in energy metabolism, we observed an overall elevated protein oxidation status (Oxyblots) at presymptomatic and symptomatic age. Carbonylated proteins were identified by mass spectrometry. Conclusions: Enhanced ROS production in mitochondria caused by Abeta has been described previously. However, the production of ROS is an inevitable consequence of mitochondrial metabolism. A disturbed equilibrium between the production of ROS and antioxidant processes leads to enhanced ROS production which has widespread consequences through oxidativemodification of proteins. Glycolytic enzymes, subunits of themitochondrial ATPase complex and other energy metabolism associated proteins were identified as targets of oxidative modifications in AD patients. Interestingly, our OxyBlot analysis revealed enhanced carbonyl modifications of proteins in APP23 mice even at presymptomatic age. Our study provides evidence for a disequilibrium in the production and detoxification of reactive oxygen species in APP23 mice long before Abeta aggregation occurs. These data resemble observations in AD patients and underline the causative role of impaired energy metabolism in AD.