The central nervous system is relatively isolated from the rest of the body; the blood-brain barrier ensures that only certain cells and molecules are permitted to pass between the body and brain. Many cell populations are specific to the brain, and even the immune systems in brain and body are relatively isolated and different from one another. Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. They can destroy pathogens and malfunctioning cells, clear up metabolic waste such as protein aggregates and cell debris, and also participate in the intricate processes of tissue regeneration. Further, microglia assist in the maintenance and function of neural networks in the nervous system.
Unfortunately microglia become ever more inflammatory with age, a maladaptive reaction to internal age-related changes such as mitochondrial dysfunction, combined with interactions between microglia and age-related changes in their environment, such as rising levels of protein aggregates and the inflammatory signals generated by senescent cells. As is a common story in aging, an aspect of cell behavior that is necessary and helpful in youth becomes harmful and maladaptive in old age. In today’s open access paper, researchers investigate one of the regulatory signal proteins involved in suppressing microglial inflammatory behavior, and demonstrate that (a) the presence of this signal declines with age, worsening microglial inflammation and (b) introducing more of the signal protein into the aged tissue environment improves microglial function.
Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice
There is little understanding of how aging serves as the strongest risk factor for several neurodegenerative diseases. 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 in mice exacerbates microglial phenotypes associated with aging, including transcriptomic changes in cell activation, changes in lysosomal-associated markers and phagocytosis, and elevated levels of stress and inflammatory proteins in the brain extracellular space measured by in vivo microdialysis. Deleting specific cellular pools of TIMP2 in vivo increases microglial CD68 and alters myelin phagocytosis. Treating aged mice with TIMP2 reverses 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 modulator of age-associated microglia dysfunction. Harnessing its activity may mitigate detrimental effects of age-associated insults on microglia function.
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