Differential Expression of Oxidative Phosphorylation Genes in Patients With Alzheimer's Disease: Implications for Early Mitochondrial Dysfunction and Oxidative Damage

Abstract

In Alzheimer's disease (AD) pathogenesis, increasing evidence implicates mitochondrial dysfunction resulting from molecular defects in oxidative phosphorylation (OXPHOS). The objective of the present study was to determine the role of mRNA expression of mitochondrial genes responsible for OXPHOS in brain specimens from early AD and definite AD patients. In the present article, using quantitative real-time polymerase chain reaction (PCR) techniques, we studied mRNA expression of 11 mitochondrial-encoded genes in early AD patients (n = 6), definite AD patients (n = 6), and control subjects (n = 6). Using immunofluorescence techniques, we determined differentially expressed mitochondrial genes NADH 15-kDa subunit (complex I), cytochrome oxidase subunit 1 (complex IV), and ATPase delta-subunit (complex V) in the brain sections of AD patients and control subjects. Our quantitative reverse transcription (RT)-PCR analysis revealed a downregulation of mitochondrial genes in complex I of OXPHOS in both early and definite AD brain specimens. Further, the decrease of mRNA fold changes was higher for subunit 1 compared to all other subunits studied, suggesting that subunit 1 is critical for OXPHOS. Contrary to the downregulation of genes in complex I, complexes III and IV showed increased mRNA expressions in the brain specimens of both early and definite AD patients, suggesting a great demand on energy production. Further, mitochondrial gene expression varied greatly across AD patients, suggesting that mitochondrial DNA defects may be responsible for the heterogeneity of the phenotype in AD patients. Our immunofluorescence analyses of cytochrome oxidase and of the ATPase delta-subunit suggest that only subpopulations of neurons are differentially expressed in AD brains. Our double-labeling immunofluorescence analyses of 8-hydroxyguanosine and of cytochrome oxidase suggest that only selective, overexpressed neurons with cytochrome oxidase undergo oxidative damage in AD brains. Based on these results, we propose that an increase in cytochrome oxidase gene expression might be the result of functional compensation by the surviving neurons or an early mitochondrial alteration related to increased oxidative damage.

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

“…Chronic stress has been shown to produce results similar to the effects of high-dose corticosteroids on mitochondrial function in intact rodent brains (35)(36)(37), suggesting that the transcriptional activity of GR in brain mitochondria is a consistent mechanism for the transduction of psychological stress into molecular pathology. Mitochondrial dysfunction in general, and complex I deficits specifically, have been shown to be associated with a number of neurodegenerative and neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, and bipolar disorder (38)(39)(40). It is possible the increase in ND-6 caused by chronic stress is a compensatory response to the mitochondrial allostatic load or overload, an idea supported by previous work showing deficits in mitochondrial function as a consequence of chronic GC exposure (15).…”

Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease

“…Mitochondrial oxidative stress occurs early in AD progression, before the onset of Aβ pathology [1,2,16,47]. Oxidative stress was reported in the mitochondria of the brain, platelets, and fibroblasts from AD patients [48,49].…”

“…Mitochondrial abnormalities have been found both in neurons and astrocytes [47,54,59], suggesting that both neurons and astrocytes may be damaged by free radicals in the AD brain. Superoxide radicals (O2 − ) may be produced in mitochondrial ETC complexes I and III (see Fig.…”

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

“…Thus, it is not surprising that mitochondrial dynamics can be greatly affected in response to physiological or environmental alterations, with severe consequences for neuronal function and survival. Indeed, altered levels of OXPHOS enzymes, particularly downregulation of respiratory complex I genes, have been found to be directly responsible for a decrease in energy production in the brains of AD patients [22,23]. As a consequence, ROS production is significantly increased, which results in Ca 2þ buffering impairment and the release of pro-apoptotic proteins.…”