Transcriptomic Analysis of Microglia in Mice Shows Greater Inflammatory Activity with Advancing Age
Microglia are innate immune cells of the brain, akin to macrophages elsewhere in the body, but equipped to undertake an additional set of tasks relating to neural function. A range of evidence strongly suggests that the progression of neurodegenerative conditions is strongly driven by greater inflammatory activity in the microglia of older individuals. This is perhaps largely due to cellular senescence, perhaps largely due to greater adoption of the aggressive M1 phenotype. Underlying causes include greater leakage of the blood-brain barrier due to the molecular damage of aging, allowing unwanted compounds and cells into the brain that will rouse an inflammatory response.
Accordingly, there is greater interest nowadays in strategies that might reduce inflammation in the brain, whether senolytic drugs targeting senescent cells, small molecules that might force microglia into the more helpful M2 phenotype, or other approaches to selectively sabotaging mechanisms of the immune response. Repair of underlying damage beyond cellular senescence that causes the chronic inflammation of aging is still a fairly low priority in the research community, alas.
Aging and Alzheimer's disease (AD) are both associated with diminished blood-brain barrier (BBB) integrity and an opening for T cell migration into the central nervous system (CNS). In the parenchyma, bidirectional crosstalk occurs between the infiltrating cells and the resident glial cells; activated microglia impair BBB function by releasing several inflammatory modulators and thus lead to hyperpermeability; and the resulting T cell infiltration, in turn, favors increased microglial activation by secreting proinflammatory cytokines or acting in a protective manner toward senescent microglia.
We performed RNA-seq analyses on microglia and astrocytes freshly isolated from wild-type and APP-PS1 (AD) mouse brains at five time points to elucidate their age-related gene-expression profiles. Our results showed that from 4 months onward, a set of age-related genes in microglia and astrocytes exhibited consistent upregulation or downregulation (termed "age-up"/"age-down" genes) relative to their expression at the young-adult stage (2 months). Most age-up genes were more highly expressed in AD mice at the same time points. Bioinformatic analyses revealed that the age-up genes in microglia were associated with the inflammatory response, whereas these genes in astrocytes included widely recognized AD risk genes, genes associated with synaptic transmission or elimination, and peptidase-inhibitor genes.
The results of this study indicate that microglia exhibit an increase in responsiveness to inflammation stimuli with age, which is reflected by the consistently elevated expression of inflammatory-response genes, whereas astrocytes appear to function as "preservers" of inflammation, which is reflected by the upregulation of peptidase-inhibitor genes upon aging.