Abstract
In aging individuals, both protective as well as regulatory immune functions are declining, resulting in an increased susceptibility to infections as well as to autoimmunity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2-deficiency in immune cell subsets has been shown to be associated with aging. Using intravital marker-free NAD(P)H-fluorescence lifetime imaging, we have previously identified microglia/myeloid cells and astrocytes as main cellular sources of NADPH oxidase (NOX) activity in the CNS during neuroinflammation, due to an overactivation of NOX. The overactivated NOX enzymes catalyze the massive production of the highly reactive which initiates in a chain reaction the overproduction of diverse reactive oxygen species (ROS). Age-dependent oxidative distress levels in the brain and their cellular sources are not known. Furthermore, it is unclear whether in age-dependent diseases oxidative distress is initiated by overproduction of ROS or by a decrease in antioxidant capacity, subsequently leading to neurodegeneration in the CNS. Here, we compare the activation level of NOX enzymes in the cerebral cortex of young and aged mice as well as in a model of vascular amyloid pathology. Despite the fact that a striking change in the morphology of microglia can be detected between young and aged individuals, we find comparable low-level NOX activation both in young and old mice. In contrast, aged mice with the human APPE693Q mutation, a model for cerebral amyloid angiopathy (CAA), displayed increased focal NOX overactivation in the brain cortex, especially in tissue areas around the vessels. Despite activated morphology in microglia, NOX overactivation was detected only in a small fraction of these cells, in contrast to other pathologies with overt inflammation as experimental autoimmune encephalomyelitis (EAE) or glioblastoma. Similar to these pathologies, the astrocytes majorly contribute to the NOX overactivation in the brain cortex during CAA. Together, these findings emphasize the role of other cellular sources of activated NOX than phagocytes not only during EAE but also in models of amyloid pathology. Moreover, they may strengthen the hypothesis that microglia/monocytes show a diminished potential for clearance of amyloid beta protein.
Highlights
Following the free-radical theory of aging, reactive oxygen species (ROS) are massively produced, e.g., >100 nM H2O2, and attack their targets in the organism randomly, indiscriminative and cumulative, generating oxidative distress [1]
NAD(P)H bound to metabolic enzymes are depicted in blue and green (τ2 between 1 and 3 ns), whereas nicotinamide adenine dinucleotide phosphate (NADPH) bound to activated NADPH oxidase (NOX) enzymes appears in red (τ2 between 3.3 and 3.9 ns, “NOX only” gate) is displayed in the right column of (B)
A reduction in numbers of phagocytes has been described in aged individuals [29], along with an impaired functionality, which has been suggested to reflect the adaptation to age-associated changes in their environment [30]
Summary
Following the free-radical theory of aging, reactive oxygen species (ROS) are massively produced, e.g., >100 nM H2O2, and attack their targets in the organism randomly, indiscriminative and cumulative, generating oxidative distress [1]. The enzymes of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family, consisting of NOX1, NOX2 (phox), NOX3, NOX4, DUOX1, DUOX2 [3], are central players leading both to oxidative eustress and distress. Their activation catalyzes the oxidative burst when abundant highly reactive O2− is produced by oxidation of molecular oxygen. O2− reacts with various small molecules leading to massive ROS production When this massive ROS production exceeds the capacities of antioxidant defense mechanisms of the tissue or when extracellular highly reactive ROS species such as H2O2 enter the cells via peroxiporins such as AQP8 [4], oxidative distress occurs, leading to tissue dysfunction and damage. This hypothesis is mainly funded on genetic studies [5], which allow conclusions on the expression levels, but not on the actual activation of these central enzymes
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