Researchers in Bonn, Germany, have identified a protein as a potential target for the treatment of Alzheimer's disease. The molecular complex is part of the immune system and a driving force for inflammatory responses of the brain. Blocking its activity may pave the way for new possibilities for therapy, the researchers report in the current issue of "Nature." The study involved scientists from Germany, Spain and the United States.
The Bonn site of the German Center for Neurodegenerative Diseases (DZNE) and the University of Bonn are leading contributors.
The complex named "NLRP3 inflammasome" is composed of several proteins and plays a key role in the immune system. It resembles a fire alarm sensor that triggers a chain reaction when activated. As a result, immune cells are mobilized and substances that foster inflammation are released. This process can be triggered by infections, which are subsequently suppressed by the immune response. However, in the case of Alzheimer's disease, the activation of the molecular alarm may have negative consequences: nerve cells are damaged and die. Ultimately, this leads to the loss of brain function and mental capabilities in humans.
Alzheimer's disease is accompanied with deposits in the brain. That these so-called "plaques" have the capability to activate the NLRP3 inflammasome had already been identified by investigating individual cells. But the exact effect on the organism was unknown. "It was unclear what consequences an increased activity of the NLRP3 inflammasome could have on the brain," explains Prof. Michael Heneka, who conducts research at both, the DZNE and the University of Bonn. Working in a team with immune researcher Eicke Latz as well as with other colleagues, Heneka has now been able to show that the protein complex does in fact play a determining role in the development of Alzheimer's disease.
Studies involved humans and mice
The researchers collected a comprehensive chain of evidences: they examined both the brains of deceased Alzheimer patients and of mice who exhibited behavioural disorders that are typically associated with Alzheimer's disease. The researchers found an activated form of the NLRP3 inflammasome in both cases.
Looking at another group of mice, the scientists examined possibilities for suppressing inflammatory reactions. To achieve this, they removed the genes that trigger production of the NLRP3 inflammasome. Therefore, these mice were no longer able to synthesize the protein complex. As a result, the animals developed only relatively mild symptoms of the disease. Moreover, their brains showed only reduced amounts of the damaging plaques.
"We have stumbled upon a critical factor in the development process of Alzheimer's. Given these findings it appears to be a very promising possibility to block the activity of the inflammasome," comments Heneka. In his view, proper pharmaceuticals might be able to stop a chain reaction that would otherwise result in the inflammation of brain cells. "At present various options are being pursued to act upon the course of the disease," says the neuroscientist. "Our results points to a new possibility. Nevertheless, we are still in the process of doing basic research."
However, the group of scientists in Bonn is already making plans for the future. Eicke Latz's team, which also made significant contributions to the latest study, has already begun to search for active components that could block the NLRP3 inflammasome. "The testing of potential substances in the laboratory would be a next step. We hope to start as early as next year," says Heneka.
- Michael T. Heneka, Markus P. Kummer, Andrea Stutz, Andrea Delekate, Stephanie Schwartz, Ana Vieira-Saecker, Angelika Griep, Daisy Axt, Anita Remus, Te-Chen Tzeng, Ellen Gelpi, Annett Halle, Martin Korte, Eicke Latz, Douglas T. Golenbock. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature, 2012; DOI: 10.1038/nature11729
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