Posted 10 July 2025 - 08:00 PM
Researchers have found that inflamed, senescent microglia prune too many synapses in the hippocampus and demonstrated that a senolytic compound can ameliorate this process in Aging Cell.
Some synapse pruning is normal
During brain development, the resident immune cells of the brain (microglia) prune unneeded synapses as a form of maintenance. This is normally a beneficial process both in young children [1] and mature adults [2], as the removal of unnecessary circuits facilitates the formation of more meaningful connections.
However, as with any of the body’s cleanup processes, disease states can send it into overdrive, causing damage. For example, during the inflammation brought on by blood sepsis, microglia tear apart functional synapses, leading to cognitive decline [3].
Like other cells, microglia can become senescent and unable to proliferate further. However, this state does not mean that they are turned off completely. While the two appear to be related, senescent microglia and disease-associated microglia are not quite the same [4].
Inflamed microglia express genes differently
This experiment began by exposing 8- to 10-week-old Black 6 mice to lipopolysaccharides (LPS) for one week in order to cause neuroinflammation. A gene expression analysis revealed that, of the 20 most upregulated genes, a full eight were related to debris clearing (phagocytosis), including genes related to Complement 1q, a compound related to synaptic pruning. Five more upregulated genes were related to senescence.
These findings were confirmed with an examination of lysosomal and activity markers. The microglia in the LPS-exposed mice were significantly more involved in phagocytosis and were also more senescent according to the p16 biomarker, which was significantly increased in the active microglia, and another examination showed that the senescent microglia in LPS-exposed mice had some morphological distinctions from the senescent microglia in the control group. Astrocyte activity was also increased by LPS. Interestingly, this phagocytosis appeared to be only limited to excitatory, rather than inhibitory, synapses, which were unaffected by this chemical.
Senolytics appear to be effective
As expected, the LPS treatment resulted in measurable levels of cognitive decline. The mice given LPS were less able to navigate a Y maze, less interested in novel objects, and less willing to navigate an open field. However, treatment with the senolytic compound ABT-737 reversed this decline, making most of their measurements indistinguishable from those of the control group.
This improvement was not due to benefits in neuroinflammation; multiple fundamental inflammatory biomarkers, including SASP biomarkers, were unaffected by ABT-737. Instead, it affected markers more directly related to senescence, such as p16 and p21. This reduction was accompanied by a decrease in the number of senescent microglia in the hippocampi of these mice.
Most importantly, ABT-737 treatment appeared to do what it set out to do. The phagocytosis of excitatory synapses was reduced in the treated mice, although, like with the behavioral analysis, not all markers were reduced to the levels of the control group. The number of dendritic spines, which decreases with LPS, was restored with ABT-737, and neuroplasticity, as measured by postsynaptic potential, also appeared to be partially restored.
These experiments used mice that were treated with an inflammatory compound, not aged mice. Further work will need to be done to determine if ABT-737 or any other senolytic is able to ameliorate the cognitive decline brought on by senescent microglia in the context of aging.
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Literature
[1] Bohlen, C. J., Friedman, B. A., Dejanovic, B., & Sheng, M. (2019). Microglia in brain development, homeostasis, and neurodegeneration. Annual Review of Genetics, 53(1), 263-288.
[2] Colonna, M., & Butovsky, O. (2017). Microglia function in the central nervous system during health and neurodegeneration. Annual review of immunology, 35(1), 441-468.
[3] Chung, H. Y., Wickel, J., Hahn, N., Mein, N., Schwarzbrunn, M., Koch, P., … & Geis, C. (2023). Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy. Science advances, 9(21), eabq7806.
[4] Rachmian, N., Medina, S., Cherqui, U., Akiva, H., Deitch, D., Edilbi, D., … & Schwartz, M. (2024). Identification of senescent, TREM2-expressing microglia in aging and Alzheimer’s disease model mouse brain. Nature neuroscience, 27(6), 1116-1124.
View the article at lifespan.io
