Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice
Brittany M Hemmer1,2,3,4,5, Sarah M Philippi1,2,3,4,5, Ana Catarina Ferreira1,2,3,4
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abstract:
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.
Insights
Tissue inhibitor of metalloproteinases 2 (TIMP2) rejuvenates the aging brain by improving microglial function. This study shows TIMP2 mitigates age-related microglial dysfunction, offering potential therapeutic strategies for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Aging is the primary risk factor for neurodegenerative diseases.
- Microglia, the brain's immune cells, exhibit detrimental changes with age, including inflammation and impaired debris clearance.
- Mediators regulating these age-related microglial changes are not well understood.
Purpose of the Study:
- To investigate the role of tissue inhibitor of metalloproteinases 2 (TIMP2) in modulating age-associated microglial dysfunction.
- To determine if TIMP2 can reverse detrimental changes in microglia observed in aging.
Main Methods:
- Utilized genetically modified mice with TIMP2 deletion to study its impact on microglial function.
- Administered TIMP2 to aged mice to assess its rejuvenating effects.
- Employed transcriptomic analysis, in vivo microdialysis, and phagocytosis assays to evaluate microglial phenotypes.
Main Results:
- TIMP2 deletion in mice worsened age-related microglial phenotypes, including increased inflammation and impaired phagocytosis.
- TIMP2 treatment in aged mice reversed these deficits, decreasing microglial activation and enhancing phagocytic capacity.
- TIMP2 influences microglial CD68 expression and myelin phagocytosis.
Conclusions:
- TIMP2 acts as a key regulator of microglial function during aging.
- TIMP2 can ameliorate age-associated microglial dysfunction.
- Targeting TIMP2 activity presents a potential therapeutic avenue for age-related neurodegenerative conditions.
