In the brain of each of us there is an invisible network that holds neurons in place and sets the rules for how they talk to one another. That network is the extracellular matrix, the protein scaffolding around cells. When we are young it is flexible, like a fresh rubber band, and it lets the connections between neurons rearrange easily whenever we learn something new. But with age something changes: the band stiffens, and memory starts to stall. For a long time the neurons themselves were thought to be at fault, but a new study points to other suspects: the helper cells known as oligodendrocytes.
Oligodendrocytes are best known for wrapping nerve fibers in insulation that speeds up signal transmission. But they also secrete matrix proteins, and with age this process spirals out of control. Researchers compared the hippocampi of young mice (3 months) and old mice (24 months) and found that in the old animals the oligodendrocytes produce far more of one particular protein: HAPLN2. This protein works like glue, binding the matrix together at the nodes of Ranvier, the bare stretches of nerve fiber where the impulse leaps from one segment to the next. In elderly people, HAPLN2 levels in the hippocampus are elevated too, especially in the zones responsible for memory.
To check whether the link between the glue and memory was merely a coincidence, the researchers ran a direct experiment. In young mice they used a virus to raise HAPLN2 levels in oligodendrocytes, and the animals became worse at remembering the location of a platform in a water maze and worse at recognizing new objects. Then, in old mice, they did the opposite and lowered the protein with a different virus. The memory of the old animals improved: they made fewer mistakes in the maze, and neurons in the CA3 region of the hippocampus became less excitable. At the same time, the activity of the brain's immune cells did not change, which means the effect is not tied to inflammation.
The result is striking because it shows that oligodendrocytes do not simply suffer from aging: they actively drive it. They secrete too much glue, and the flexible network of memory turns rigid. By lowering the level of a single protein, the scientists were able to soften that network and give old mice back some of their cognitive youth.
Today HAPLN2 can be seen as a target for developing drugs against age-related memory impairment and, possibly, neurodegenerative diseases. The glue that has set hard might be dissolved, and then the network of memory could become flexible again, as it was in youth.
The nodes of Ranvier, where HAPLN2 accumulates, are gaps in the myelin sheath about 1 micrometer long. That is exactly where the nerve impulse "leaps," speeding up tens of times over. In older people, there are fewer such stretches, and the signal slows down.
In Greg Egan's novel Permutation City, characters control their own biochemistry to change their personalities. Manipulating the extracellular matrix, as in this work, is a first step toward influencing memory through the molecular environment of neurons rather than through the neurons themselves.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.