Loss of ferritin‐positive microglia relates to increased iron, RNA oxidation, and dystrophic microglia in the brains of aged male marmosets

Abstract

number: 308515 Microglia are cells that protect brain tissue from invading agents and toxic substances, first by releasing pro-inflammatory cytokines, and thereafter by clearing tissue by phagocytosis. Microglia express ferritin, a protein with ferroxidase activity capable of storing iron, a metal that accumulates in brain during aging. Increasing evidence suggests that ferritin plays an important role in inflammation. However, it is not known if ferritin/ iron content can be related to the activation state of microglia. To this end, we aimed to delineate the role of ferritin in microglia activation in a non-human primate model. We analyzed brains of male marmosets and observed an increased density of ferritin+ microglia with an activated phenotype in hippocampus and cortex of old marmosets (mean age 11.25 ± 0.70 years) compared to younger subjects. This was accompanied by an increased number of dystrophic microglia in old marmosets. However, in aged subjects (mean age 16.83 ± 2.59 years) the number of ferritin+ microglia was decreased compared to old ones. Meanwhile, the content of iron in brain tissue and cells with oxidized RNA increased during aging in all hippocampal and cortical regions analyzed. Abundant amoeboid microglia were commonly observed surrounding neurons with oxidized RNA. Notably, amoeboid microglia were arginase1+ and IL-10+, indicative of a M2 phenotype. Some of those M2 cells also presented RNA oxidation and a dystrophic phenotype. Therefore, our data suggest that ferritin confers protection to microglia in adult and old marmosets, while in aged subjects the decline in ferritin and the increased amount of iron in brain tissue may be related to the increased number of cells with oxidized RNA, perhaps precluding the onset of neurodegeneration.

Dystrophic microglia are a disease associated microglia morphology in the human brain

“…In marmosets, it was found that the number of dystrophic microglia increased with age in both the limbic cortex and neocortex. However, they found this increase peaked in late middle age marmosets and declines in the oldest aged marmosets [30]. These results are in contrast to our current study, where we saw the total number of dystrophic microglia increase linearly with age.…”

“…Our quantitative methods to measure FTL in LATE-NC cases found that a greater amount of the dystrophic microglia was labeled with FTL in comparison to hypertrophic microglia. Recent work in aged marmosets found that FTL labeled both an activated and dystrophic phenotype [30]. Our work is not in disagreement, as we, too, can identify FTL labeled hypertrophic microglia.…”

Translesion synthesis by AMV, HIV, and MMLVreverse transcriptases using RNA templates containing inosine, guanosine, and their 8-oxo-7,8-dihydropurine derivatives

“…On a different note, oxidative damage of RNA is a topic that has increasingly captured attention due to its potential role in the development/progression of disease [14][15][16][17]. Oxidized RNA has been shown to occur in various types of RNA including rRNA [18], miRNA [19], or mRNA [20], and intracellular mechanisms in charge of diminishing the impact of oxidation have been reported [21][22][23][24].…”

Experimental and theoretical rationalization for the base pairing abilities of inosine, guanosine, adenosine, and their corresponding 8‐oxo‐7,8‐dihydropurine, and 8‐bromopurine analogues within A‐form duplexes of RNA

“…Oxidative stress can lead to the formation of lesions at the nucleobases of DNA and RNA, with the latter gaining interest due to its potential role in the development/progression of disease. [1][2][3][4][5][6] Among the four canonical nucleobases, purine rings have the lowest redox potential (G < A < U ≈ C) [7,8] thus making them substrates that more readily undergo oxidation in the presence of reactive oxygen species (ROS), which may be generated from exogenous and/or endogenous sources. [9] Furthermore, oxidative damage has been reported to impact RNAs of different sizes and with distinct functions, for example, miRNA, [10,11] rRNA, [12] and mRNA.…”