Youth-associated protein TIMP2 restores microglial function in aged mice

Researchers at the Icahn School of Medicine at Mount Sinai have identified a role for the protein TIMP2 in maintaining healthy function of microglia, the brain's resident immune cells. The study, published August 12 in Nature Communications, found that loss of TIMP2 caused microglia to develop features associated with aging and neurodegeneration, while restoring TIMP2 in aged mice improved microglial debris clearance and reduced markers of inflammation and cellular stress.

Microglia play essential roles in clearing cellular debris, supporting neural circuits, and responding to injury. With age, these cells can become less efficient and adopt states that contribute to inflammation and impaired brain function. Aging is the strongest known risk factor for Alzheimer's disease and other neurodegenerative disorders, yet the biological changes underlying this vulnerability remain incompletely understood.

The research team, led by corresponding author Joseph M. Castellano and first author Brittany Hemmer, used multiple mouse models including mice lacking TIMP2 throughout the body and mice with selective TIMP2 deletion in microglia or neurons. They employed single-nucleus RNA sequencing, advanced imaging, in vivo microdialysis, and functional assays to profile microglial states and debris-handling capacity.

Deleting TIMP2 caused microglia to exhibit characteristics commonly associated with aging and brain injury, including changes in activation markers, impaired debris clearance, and molecular signatures of cellular senescence. Loss of TIMP2 was also accompanied by increased levels of inflammatory and stress-related proteins in the brain's extracellular environment.

The researchers then administered systemic injections of TIMP2 to aged mice. Treatment shifted microglia away from proinflammatory states and improved their capacity to clear debris. The results suggest TIMP2 helps regulate how microglia respond to challenges in the brain, supporting functions that maintain a healthy neural environment while limiting potentially harmful responses.

Castellano noted that previous work identified TIMP2 as a regulator of synaptic plasticity through the extracellular matrix, suggesting this factor sits at the intersection of several processes critical for normal brain function. The findings point to a potential molecular link between systemic youth-associated factors and innate immune cell function in the aging brain.

The researchers emphasize that the study was conducted in mice and that further research is needed to determine whether the findings translate to humans. Additional studies are also required to assess whether TIMP2 or the pathways it regulates could eventually be targeted to modify age-related changes in the brain.

The work was published in Nature Communications (DOI: 10.1038/s41467-026-74906-z) and supported by the Mount Sinai Health System.