NLRP3 inflammasome activation drives tau pathology Ising, Christina Venegas Maldonado, Carmen Jesica 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 Latz, Eicke Buée, Luc Heneka, Michael T. This work was supported by funding from the Deutsche Forschungsgemeinschaft (DFG) to C.I. (IS 299/3-1) and under Germany’s Excellence Strategy – EXC2151 – 390873048. R.K. received funding from a NIH grant (R01 AG054025), and D.G. and M.T.H. received further funding from a NIH grant (R01 AG059752-02). Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline1. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release2. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice3, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation. 2026-02-24T08:24:31Z 2026-02-24T08:24:31Z 2019-11-20 journal article Ising, C., Venegas, C., Zhang, S. et al. NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673 (2019). https://doi.org/10.1038/s41586-019-1769-z https://hdl.handle.net/10481/111431 10.1038/s41586-019-1769-z eng http://creativecommons.org/licenses/by-nc-nd/3.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Springer Nature