In the matter of the aging of the brain, researchers are increasingly turning their attention to inflammatory dysfunction in the immune system of the central nervous system, particularly the innate immune cells known as microglia, analogous to macrophages elsewhere in the body. Neurodegenerative conditions are characterized by excessive unresolved inflammation in brain tissue, a state that is disruptive to tissue structure and function, altering cell behavior for the worse. As the paper noted here illustrates, research into how this inflammation arises, and how dysfunction emerges in microglia, is proceeding one gene at a time, looking for important regulatory mechanisms and points of intervention.
There is little understanding of how aging serves as the strongest risk factor for several neurogenerative diseases. Specific neural cell types, such as microglia, undergo age-related maladaptive changes, including increased inflammation, impaired debris clearance, and cellular senescence, yet specific mediators that regulate these processes remain unclear.
The aged brain is rejuvenated by youth-associated plasma factors, including tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown acts on the extracellular matrix (ECM) to regulate synaptic plasticity. Given emerging roles for microglia in these processes, we examined the impact of TIMP2 on microglial function.
We show that TIMP2 deletion exacerbates microglial phenotypes associated with aging, including transcriptomic changes in cell activation, increased microgliosis, and increased levels of stress and inflammatory proteins measured in the brain extracellular space by in vivo microdialysis. Deleting specific cellular pools of TIMP2 in vivo increased microglial activation and altered myelin phagocytosis.
Treating aged mice with TIMP2 reversed several phenotypes observed in our deletion models, resulting in decreased microglial activation, reduced proportions of proinflammatory microglia, and enhanced phagocytosis of physiological substrates. Our results identify TIMP2 as a key modulator of age-associated microglia dysfunction. Harnessing its activity may mitigate detrimental effects of age-associated insults on microglia function.
Link: https://doi.org/10.1101/2025.05.20.655226
View the full article at FightAging
