Die Rolle von Mikroglia in der Entstehung von Amyloid-beta-induzierten Tau-Ablagerungen und deren Verbreitung
Zusammenfassung der Projektergebnisse
Alzheimer's disease is the most common form of dementia worldwide, characterized by the deposition of amyloid-beta in the extracellular space and tau in the neurons. In addition, a chronic neuroinflammation is present in both patient and animal models, which is believed to contribute to the pathology. However, the connections between these three characteristics of the disease have so far only been insufficiently clarified. Microglia, the innate immune cells of the brain, are chronically activated in Alzheimer's disease. Activation of the NLRP3 inflammasome is an important acute defense mechanism in microglia that is no longer switched off in Alzheimer's disease. At least in part, this can be attributed to the presence of amyloid-beta. Since tau pathology is also negatively influenced by microglia activation and an injection of amyloid-beta into the brain of mice can induce tau deposits, the question arises to what extent (amyloidbeta) activated microglia play a role in the induced pathology. Our data generated within this project indicate that the NLRP3 inflammasome has a key function here, since loss of inflammasome components can prevent the formation of tau deposits after amyloid-beta injection. Furthermore, work by other groups shows that taucontaining extracellular vesicles, which can be released by e.g. microglia, play a role in the spread of tau deposits throughout the brain. Our data suggest that this vesicle secretion is not increased by chronically activated microglia, but that the NLRP3 inflammasome could also be important here, since inflammasome components were detectable in the extracellular vesicles when the NLRP3 inflammasome was activated. Taken together, our data therefore indicate that the NLRP3 inflammasome is of strategic importance in Alzheimer's disease and its inhibition could be a possible new therapeutic approach.
Projektbezogene Publikationen (Auswahl)
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NLRP3 inflammasome activation drives tau pathology. Nature, 575(7784), 669-673.
Ising, Christina; Venegas, Carmen; Zhang, Shuangshuang; Scheiblich, Hannah; Schmidt, Susanne V.; Vieira-Saecker, Ana; Schwartz, Stephanie; Albasset, Shadi; McManus, Róisín M.; Tejera, Dario; Griep, Angelika; Santarelli, Francesco; Brosseron, Frederic; Opitz, Sabine; Stunden, James; Merten, Maximilian; Kayed, Rakez; Golenbock, Douglas T.; Blum, David ... & Heneka, Michael T.
