Differential expression of mitochondrial energy producing genes in AD brains compromise ATP Synthesis and neuronal viability and stimulate inflammatory pathways and ROS synthesis

Abstract

AbstractBackgroundMitochondrial dysfunction is a critical component in the pathogenesis of Alzheimer’s disease (AD) where deficits in oxidative capacity and energy production have been observed.MethodA focused array of 84 genes involved in energy production in mitochondria was used to determine whether changes in these genes compromise mitochondrial function and other important biological processes or pathways.ResultWe find that a majority of these genes is down‐regulated in AD brains. These AD‐related gene expression changes are seen to affect a number of biological functions and pathologic conditions, including metabolism of nucleotides, synthesis of ATP, and nerve cell viability. The most affected complexes appear to be RCI and RCV. Particularly important are NDUFA10, ATP5PD, and ATP5F1B. Others to note are UQCRC1, a component of RC III, and COX6A1, a component of RC IV. Interestingly, GAPDH, a gene seen to be down regulated in our previous study of mitochondrial biogenesis, is also found to be downregulated in the current study. Lastly, BCS1L, a ubiquinol‐cytochrome c reductase complex (RC III) chaperone involved in assembly of RC III is one of the more substantially up‐regulated genes (+8.02‐fold) in AD brains.ConclusionThere are significant gene expression changes in a small number of nuclear encoded mitochondrial genes involved in energy production in AD brains. These impact nucleotide synthesis and pro‐ and anti‐inflammatory pathways and reflect the mitochondrial dysfunction associated with neuronal cell death and AD..