TREM2: A booster against Alzheimer's?

A protein may hold potential starting points for a therapy against Alzheimer's disease. The current finding is that the higher the TREM2 level, the better the body's immune cells seem to cope with the disease.

The inconspicuous protein TREM2 has an important function: it drives the immune cells of the brain to peak performance. The higher the concentration of TREM2 in Alzheimer's patients, the slower their memory deteriorates, researchers have found. This offers starting points for future therapies in which the function of the protein could be artificially stimulated.

The mode of action of TREM2 is closely linked to microglial cells. These are the immune cells of the brain; they can be thought of as a patrol that travels around the brain disposing of cellular waste products. This includes deposits in the brain that are typical of Alzheimer's disease - such as amyloid plaques. The microglia cells can literally surround them and destroy them in a targeted manner. In this way, they apparently prevent damage to the brain.

The TREM2 protein acts as a switch: if it is flipped, a signal is sent to the microglia cells to increase their activity. TREM2, a protein, is produced by the microglia cells themselves. The highest concentrations of TREM2 are found in the hippocampus, the brain region responsible for memory and learning. It is striking that the TREM2 concentration increases with age - presumably because more cellular waste products are produced in the brain with age and the microglia cells therefore have more to do. At the same time, the TREM2 level in the cerebrospinal fluid indicates the condition of the microglia.

TREM2 normally occurs as a receptor on the surface of microglia - and because it can detach from there and then be detected in the cerebrospinal fluid, scientists got onto its trail.

Because of its detectability in the cerebrospinal fluid, TREM2 could also be used as a warning sign in the early stages of Alzheimer's disease. Scientists from the DZNE have discovered that the microglia become particularly active from the moment when the first amyloid proteins clump together - that is precisely the moment when brain damage begins. At this early stage, patients do not yet show any symptoms, and it can take a full two decades before the first memory problems appear. However, because by this later stage the brain damage has progressed so far that it is too late for therapy, early detection plays a particularly important role. TREM2 could take over this role, because from the moment of increased microglial activity, a higher TREM2 level can also be measured.

And TREM2 has another signaling effect: the faster the level rises over the years, the slower pathological processes progress in the brain. Memory remains more stable, and the hippocampus shrinks less.

Scientists at DZNE succeeded in promoting the protective function of TREM2. They developed an antibody that stabilizes TREM2 and thus increases its signaling to protective properties. The microglial cells rejuvenate, they proliferate again, increase their metabolism and start to degrade plaques again. This approach is so promising that initial studies in humans already started.