We are very much interested in how immune cells of the brain, the microglia, contribute to Alzheimer’s disease pathology. Subtle changes (mutations) in genes expressed exclusively in microglia were associated with a strongly increased risk for developing Alzheimer’s disease late during aging. We made use of this finding and searched how these mutations may affect microglial function. We quickly found that these mutations strongly reduced the capability of microglia to respond and fight against the accumulation of toxic amyloid plaques; thus, they lost activities, which normally protect our brain during aging. This finding opened up a completely new avenue toward novel therapeutic treatment strategies. We developed antibodies that boost the protective activities of microglia. These antibodies are directed to an important microglial protein called TREM2, which turned out to be an essential switch required for microglia to respond to pathological challenges in the brain. When microglia recognize, for example, an amyloid plaque, this switch turns on a cellular program, which allows the microglia to actively fight against this pathological challenge. Once they have done their job, the switch is turned off by a very simple mechanism: it is simply cut by a scissorlike enzyme. We now have developed mouse models that express either uncleavable TREM2, which should be super active, or only its cleaved product, which should be inactive. We now are investigating how these mouse models handle amyloid plaque pathology, with the goal to better understand our translational efforts to boost protective TREM2 functions.
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.