Signaling Function of TREM2 Cleavage Products, Which are Affected by Agonistic Antibodies to the Stalk Region


Alzheimer’s disease (AD) is an uncurable neurodegenerative disorder that affects elderly people with a very high probability. Current treatment strategies reduce the disease-characterizing amyloid deposits from the brain; however, they fail to stabilize memory. We have developed strategies that allow boosting the protective activity of the brain’s immune cells—the microglia. This targets a trigger on the immune cell’s surface and turns it on, which in return initiates a defensive genetic program. Induction of this pathway is carefully regulated by cutting the trigger with a scissor-like enzyme, which terminates its activity. We developed a therapeutic antibody, which binds close to the site where the scissor cuts, and thus prevents its access, which leads to a stabilization of the trigger and consequently a boost of the defensive program of microglia. Such protective microglia recognize amyloid plaques more quickly and can rapidly remove them immediately after they are deposited. We think we are providing a very valuable additional strategy to prevent or slow AD. However, we need to know what happens in the brain after prolonged activation of microglia. We cannot exclude that continuous activation of microglia may exhaust these cells and probably even reduce their survival in the long run. We, therefore, want to induce long-lasting maximal stimulation of the trigger by genetically modifying it so that the scissor-like enzyme is not able to cleave it anymore. This would allow us to follow beneficial but also detrimental consequences of long-lasting treatments, which will be required to slow the progression of AD successfully. To follow the consequences in living animals, we are using imaging methods, which we also apply in parallel in humans at our institute to visualize amyloid deposition.

Funding to Date



Studies of Innate Immune Pathology, Translational


Christian Haass, Ph.D.

Kai Schlepckow, Ph.D.