Kimberly A Kerns

Background: In the past decade, Alzheimer's disease (AD) researchers have found that the formation of amyloid aggregates occurs after dysregulation of respiratory chain activity. Objective: Using our developing mathematical model to identify potential therapeutic targets for AD treatment. Methods: We have constructed a mathematical model for AD that incorporates enzyme activities and kinetics, and protein and mRNA expression levels. Results: Our analyses of gene expression in AD brains provide complimentary evidence that changes in mitochondrial energy production and biogenesis accompany AD pathogenesis. Using this data, we created a mitochondrial model of electron transport chain supercomplex assembly. Conclusions: By carrying out sensitivity analyses of responses to oxidative stress and effects of gene expression on energy production, we demonstrate how oxidative stress and energy deficits change the initial antioxidant defense system and impact the progression of AD. We investigated the impact of gene expression changes in 9 genes as new therapeutic options via metabolic flux analysis of supercomplex assembly. Through careful analysis, we propose that UQCRC1 may be an effective therapy option for in vitro AD treatment testing.

Background: We have previously reported that a subset of nuclear-encoded mitochondrial genes involved in mitochondrial biogenesis was differentially expressed in Alzheimer's disease (AD) brains. These were associated with compromised biological pathways of mitochondria such as mitochondrial morphology, fragmentation, transmembrane potential and neuronal cell death. Objective: To use an array of energy production genes to determine whether expression changes compromise mitochondrial function and other important biological processes or pathways impacting the development of AD. Methods: RT2-PCR arrays were used to assess expression of mitochondrial energy production genes in AD brains. A subset of genes of interest was identified using Ingenuity Pathway Analysis. Expression values from this filtered group of genes were included in a mathematical model being developed to identify potential therapeutic targets for AD. Results: A majority of these genes was downregulated in AD brains. These AD-related gene expression changes were seen to affect a number of biological functions and pathologic conditions, including synthesis of ATP, generation of reactive oxygen species (ROS), and nerve cell viability. Most importantly, UQCRC1, an essential component of RCIII that is also involved in efficient assembly of the mitochondrial respirasome, was identified by our array analysis and, subsequently implicated by inclusion in our mathematical model to be a potential therapeutic target. Conclusions: There are significant gene expression changes in a small number of nuclear-encoded mitochondrial genes involved in energy production in AD brains. These affect ROS and nucleotide synthesis and pro- and anti-inflammatory pathways and reflect the mitochondrial dysfunction associated with neuronal cell death and AD.