Youth-Linked Protein Rejuvenates Aging Brain's Immune Cells in Mice, Study Finds

Researchers at the Icahn School of Medicine at Mount Sinai have identified a role for TIMP2, a protein associated with youth, in helping microglia — the brain's resident immune cells — maintain healthier function as the brain ages. The findings, published in Nature Communications, come from experiments in mice.

Microglia normally protect brain health by clearing cellular debris, supporting neural circuits and responding to injury, but they become less efficient with age and can shift into states linked to inflammation. To study TIMP2's role, the researchers used several mouse models: some lacked TIMP2 throughout the body, while others had the protein selectively removed from either microglia or neurons, and gene activity was analyzed using single-nucleus RNA sequencing of brain tissue. When TIMP2 was removed, microglia developed several features commonly linked to aging and neurodegeneration: the cells became less capable of clearing debris and showed molecular signatures associated with cellular senescence.

Restoring TIMP2 had the opposite effect. After systemic injections of TIMP2 into aged mice, microglia shifted away from pro-inflammatory states and became better at clearing debris, the researchers reported. Levels of inflammatory and stress-related proteins in the brain's extracellular environment were also higher when TIMP2 was absent, measured using a technique called in vivo microdialysis.

Aging is the strongest known risk factor for Alzheimer's disease and other neurodegenerative disorders, though researchers do not fully understand the biological changes involved. Corresponding author Joseph Castellano said the findings point to a possible molecular connection between systemic factors associated with youth and the function of immune cells in the aging brain. Because the experiments were conducted in mice, the researchers say further study is needed to determine whether the same findings apply to humans.