Mitochondrial energy production genes affecting reactive oxygen species and ATP synthesis, inflammatory pathways, and neuron viability are differentially expressed in brains of Alzheimer's disease patients

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Abstract
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.
Funding Information
  • Commonwealth Health Research Board (#274-08-17)
  • Alzheimer's and Related Diseases Research Award Fund (ARDRAF#23-3)

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