Telomere shortening caused microglia to release DLK1 and disrupt myelin in aging models

In mice with shortened telomeres, microglia were the source of DLK1, a protein that inhibits the maturation of myelin-producing cells

In an article published in Neuron on August 11, the authors separately examined the source and effects of the soluble form of DLK1, sDLK1. In the telomere model, excess sDLK1 in the cerebrospinal fluid came mainly from microglia. In other experiments, the protein itself delayed the maturation of myelin-producing cells.

Telomeres are protective regions at the ends of chromosomes. The authors bred mice without Terc for three generations. This gene is required for telomerase, the enzyme that maintains telomeres. In third-generation mice, the telomere signal was lower in brain microglia. Microglia are immune cells that monitor tissue health. In these mice, they acquired features of cellular senescence. At the same time, gene activity changed in oligodendrocytes, the cells that form the myelin sheath around nerve fibers.

A 2023 study had already shown that neuron-derived DLK1 can delay the maturation of progenitor cells that develop into oligodendrocytes. The authors of the current study tested whether microglia with features of cellular senescence could become a source of the same protein.

A white matter map of aged mice published in July had already identified inflamed microglia with features of cellular senescence near myelinated fibers. The current experiments examine one signal through which such microglia may affect myelin-producing cells.

In cultures of microglia derived from human stem cells, the authors identified DLK1 among the proteins associated with features of cellular senescence. DLK1 is normally anchored in the cell membrane, but its soluble form, sDLK1, is released into the surrounding environment. In mice with short telomeres, sDLK1 levels increased in the cerebrospinal fluid. When the researchers used a drug to eliminate more than 90% of the microglia in the hippocampus, the excess protein disappeared. This result showed that, in this model, microglia were the main source of the elevated sDLK1 in the cerebrospinal fluid.

The authors then tested the effects of the protein itself. They increased sDLK1 levels in the mouse brain using a modified virus that delivered the sDLK1 gene to cells. Two months later, levels of the myelin proteins MBP and MOBP had decreased, and oligodendrocyte progenitor cells were more likely to remain at an early developmental stage. Adding recombinant sDLK1 to cultures of human cells produced the same result: the cells developed into mature oligodendrocytes more slowly.