When young donor myeloid cells are transplanted into aging mouse brains, they quickly adopt aging phenotypes. In contrast, old myeloid cells transplanted in young brains take on a more youthful aspect. These findings, which establish the brain’s local environment as the primary driver of microglial aging, are reported in a new preprint published on bioRxiv earlier this week. The work was done by a team of scientists from Calico Life Sciences, Stanford University, Broad Institute of MIT and Harvard, and other collaborators.
The study focused on microglia, the immune cells of the central nervous system and one of the most affected cell types in aging brains. In the preprint, which is titled “Heterochromic myeloid cell replacement reveals the local brain environment as key driver of microglia aging,” the scientists describe “a scalable, genetically modifiable system for in vivo heterochromic myeloid cell replacement” that they used to “establish the local environment, rather than cell-autonomous programming, as a primary driver of microglia aging phenotypes.”
Full details of the methods that the scientists used are provided in the paper but essentially the team performed single-cell transcriptomics and mapping of immune cell proteins from the cortex and cerebellum of young and aged mice. This data let the team identify microglia, macrophages, granulocytes, T-cells, and natural killer cells as well as “differential gene expression patterns between cerebellar and cortical microglia at young baseline.” The team also designed a protocol for replacing the brain cells in young and aged mice that relied on bone marrow conditioning and treatment with a CSF1R inhibitor. The mice used in the study were aged three- and 18-months.
Analysis of the cells that were isolated from the cortex and the cerebellum of mice following microglia replacement showed that “reconstituted myeloid cells adopt region-specific transcriptional, morphological, and tiling profiles characteristic of resident microglia,” they wrote. According to one set of results reported in the paper, young cells transplanted into the cortical region of older mice brains showed changes in gene expression and underwent “significant” morphological changes seen with aged cortical WT microglia including reduced surface area, shorter branches, and decreased branches. These same changes were not present in microglia in the cerebellum suggesting that “local cues within the CNS drive region-specific, aging-line changes in both gene expression and morphology.”
Other findings reported in the paper include the identification of “STAT1-mediated signaling as one axis controlling microglia aging.” Both wild-type and transplanted microglia in aged brains showed “strongly induced interferon response” including increased upregulation of STAT1. Tests revealed blocking this protein’s signaling “prevented aging trajectories in reconstituted cells.”
Lastly, their experiments pointed to natural killer cells as “necessary drivers of interferon signaling in aged microglia.” This is significant because the build up of this immune cell type is linked to impaired cognition in aging humans and mice. And further, its depletion in models of Alzheimer’s disease improves cognition and reduces neuroinflammation.
Additional studies are needed to flesh out the findings reported in the current preprint. In fact, the scientists note some outstanding questions that they have related to the research. For example, the study does not explore the effects of natural cell depletion on other cell types in the brain such as oligodendrocytes. Or how myeloid cells in other brain niches respond to signals in their local environments.
However, their work could be the basis for a new crop of studies focused on “modulators of microglial aging” as well as potential targets for developing novel age-related therapeutics.