NLRP3 inflammasome activation drives tau pathology

Christina Ising, Carmen Venegas, Shuangshuang Zhang, Hannah Scheiblich, Susanne V. Schmidt, Ana Vieira-Saecker, Stephanie Schwartz, Shadi Albasset, Róisín M. McManus, Dario Tejera, Angelika Griep, Francesco Santarelli, Frederic Brosseron, Sabine Opitz, James Stunden, Maximilian Merten, Rakez Kayed, Douglas T. Golenbock, David Blum, Eicke LatzLuc Buée, Michael T. Heneka

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)669-673
Number of pages5
JournalNature
Volume575
Issue number7784
DOIs
StatePublished - Nov 28 2019

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Cite this

Ising, C., Venegas, C., Zhang, S., Scheiblich, H., Schmidt, S. V., Vieira-Saecker, A., Schwartz, S., Albasset, S., McManus, R. M., Tejera, D., Griep, A., Santarelli, F., Brosseron, F., Opitz, S., Stunden, J., Merten, M., Kayed, R., Golenbock, D. T., Blum, D., ... Heneka, M. T. (2019). NLRP3 inflammasome activation drives tau pathology. Nature, 575(7784), 669-673. https://doi.org/10.1038/s41586-019-1769-z