TIMP2, a protein linked to young blood, altered brain immune cell function in old mice

TIMP2, a protein linked to young blood, altered brain immune cell function in old mice

In a paper published on August 12, researchers administered TIMP2 to 20-month-old mice eight times on alternate days. The hippocampus subsequently contained fewer microglia expressing CD68, a lysosomal protein. Lysosomes are cellular compartments that break down engulfed material. Experiments with myelin and synaptic fragments produced different results.

Microglia are immune cells in the brain. They respond to damage and engulf cellular debris, myelin, which is the fatty sheath around nerve fibers, and fragments of synapses, the sites where neurons communicate. Lysosomes then break down this material.

In a 2017 study of umbilical cord plasma, TIMP2 was more abundant in umbilical cord plasma, young mouse plasma, and the young hippocampus. Administering the protein to old mice altered measures of plasticity and memory. In a 2023 study, researchers linked neuron-derived TIMP2 to the extracellular matrix, a network of proteins surrounding synapses. Microglia also modify this network and clear material from around neurons, so the new study examined how they respond to TIMP2.

The authors first deleted the Timp2 gene throughout the mouse, then deleted it separately in microglia and neurons. Loss of the protein increased CD68 levels in microglia. When Timp2 was deleted only in microglia, the cells were less effective at taking up and clearing labeled myelin. These experiments showed that TIMP2 produced by microglia themselves affects how the cells process myelin.

The researchers then administered TIMP2 to old mice. RNA analysis in individual cell nuclei showed a smaller proportion of a microglial subgroup expressing genes associated with inflammation, oxidative stress, and cellular senescence.

Phagocytosis, the cellular uptake and breakdown of material, produced different results depending on the type of material. In brain sections, microglial lysosomes contained more VGLUT1, a protein marker of fragments from synapses that transmit excitatory signals. The authors used this marker to measure uptake of the synaptic material. Microglia isolated after treatment took up less labeled myelin than microglia from control animals. These measurements capture different aspects of how microglia process synaptic material and myelin.