Microglia with signs of cellular senescence and inflammation accumulate in the white matter of old mice
Microglia with signs of cellular senescence and inflammation accumulate in the white matter of old mice
On July 13, a Mayo Clinic team published a map of the old mouse brain that shows the position of individual cells within the tissue. Near the hippocampus, the researchers identified a microglial population with signs of inflammation, cellular stress, and molecular signals associated with neurodegeneration. In old female mice, two systemic interventions reduced these signals and altered cell morphology.
White matter consists of myelinated nerve fibers that connect different regions of the brain. The fornix, a bundle of fibers involved in transmitting memory signals, runs near the hippocampus. In an article published in Nature Aging on July 13, researchers identified a microglial population in this region that showed signs of cellular senescence and inflammation in old animals.
Microglia are the immune cells of the brain. They clear cellular debris and participate in responses to injury. In old mice, cells in the identified population more often expressed p16 and p21, proteins associated with cell cycle arrest, and GAL3, a marker of stress in lysosomes, which are intracellular recycling systems. They also expressed genes active in an inflammatory microglial state associated with neurodegeneration.
A single marker is not sufficient to identify cellular senescence. The authors defined this group using a combination of inflammatory molecules, signs of lysosomal stress, and cell morphology. The population was almost absent in young mice.
A 2021 study showed that age-associated microglia in white matter gather around damaged myelin and clear its remnants. This clearance may benefit the tissue. The new study describes a more inflammatory subset of this population, in which lysosomal stress occurs together with inflammation.
The team compared two systemic interventions. In genetically modified mice, AP20187 induced the death of cells with active p16. Venetoclax inhibited BCL2, a protein that helps damaged cells survive. In old female mice, both treatments reduced several age-associated molecular signals and altered microglial morphology. AP20187 also made the spatial distribution of the cells more similar to that observed in young mice. Across the different experiments, each group included approximately four to eight mice, and molecular responses varied more among individual male mice. Both interventions acted throughout the body and could have affected cells outside the identified population.
In another study published in 2025, a senolytic accelerated myelin repair after focal damage in young and middle-aged mice, but had no such effect in old mice. The age of the animal altered the response to treatment.
In this series of experiments, the authors measured spatial cell maps, molecular signals, and microglial morphology. A subsequent experiment should assess memory, signal transmission along nerve fibers, and myelin repair. Venetoclax also altered microglia in young female mice. A senolytic intended for the brain must distinguish the state of a cell, its location within the tissue, the age of the organism, and the function that the cell performs in that tissue.