Gene Expression Profile of the Mitochondrial Calcium Uniporter and Antioxidant Enzymes throughout the Brain During Alzheimer’s Disease

Abstract

In 2023, there were an estimated ~6.7 million Americans ≥65 years old living with Alzheimer’s disease (AD), a prominent form of dementia. Development of AD has been associated with impaired blood flow to and throughout the brain. In turn, there is diminished delivery of oxygen and nutrients in tandem with reduced clearance of neurotoxic cellular byproducts, notably reactive oxygen species (ROS; e.g., superoxide, peroxide/hydroxyl radicals). As a primary source of cerebrovascular ROS, endothelial mitochondria become progressively dysfunctional in producing ATP relative to ROS in response to aging and cell senescence. A primary mechanism is described by enhanced Ca2+ sequestration into the mitochondrial matrix through the mitochondrial Ca2+ uniporter (MCU) complex ( Mcu, Mcub, Mcur1, Micu1, Micu2, Micu3) and a resulting overproduction of ROS up to conditions of cell death. The primary antioxidants that eliminate ROS are superoxide dismutase ( Sod2), catalase ( Cat), and glutathione peroxidase ( Gpx1). We tested the hypothesis that upregulation of the MCU complex occurs in tandem with decreasing expression of antioxidant enzymes throughout the brain during progression of AD pathology. To investigate this hypothesis, we employed a triple mutation mouse model of AD ( 3xTg-AD) comprising young control (YC; 1-2 mo), mild cognitive impairment (MCI; 4-5 mo), presence of extracellular amyloid-β plaques (Aβ; 6-8 mo), and extracellular amyloid-β plaques with neurofibrillary tangles composed of tau (AβT; ≥12 mo) [n ≥3 per group, males & females]. Quantitative polymerase chain reaction (qPCR), Nanostring, and/or RNA-Seq have been performed on cortex, hippocampus, cerebral vessels, cerebrovascular endothelial cells (ECs), and peripheral blood. Primary highlights of our findings for each of the AD study groups are described below. With detectable presence of all target genes throughout tissue compartments, the YC group is particularly characterized by a higher MCU complex and antioxidant expressions in cortex relative to hippocampus. During the MCI phase, the MCU complex and Cat are upregulated in ECs relative to the YC group. Upon onset of AD (Aβ stage), there is a downregulation and upregulation of MCU complex in the brain and peripheral blood respectively. Further, Gpx1 expression is upregulated in ECs in the Aβ group. Relative to YC, the MCU complex and antioxidants are downregulated in cortex but generally stable in hippocampus during AβT conditions with exception of upregulation in peroxide scavenger mRNAs Cat and Gpx1. In contrast for ECs, the MCU complex increases, while Cat and Gpx1 decrease, in the AβT group relative to YC. Altogether, these findings support an intricate expression profile of the MCU complex and key antioxidant enzymes across brain tissue and cell compartments preceding and accompanying AD pathology. A remarkable observation is that expression profiles of cerebrovascular vessels and blood indicate MCI and early onset of AD, whereas those of the cortex and hippocampus best accompany late-stage AD pathology. This research was supported by the National Institutes of Health (R01AG073230). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.