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 Latz, Luc Buée and Michael T. Heneka ()
Additional contact information
Christina Ising: University Hospital of Bonn
Carmen Venegas: University Hospital of Bonn
Shuangshuang Zhang: University Hospital of Bonn
Hannah Scheiblich: University Hospital of Bonn
Susanne V. Schmidt: University Hospital Bonn
Ana Vieira-Saecker: University Hospital of Bonn
Stephanie Schwartz: University Hospital of Bonn
Shadi Albasset: University Hospital of Bonn
Róisín M. McManus: University Hospital of Bonn
Dario Tejera: German Center for Neurodegenerative Diseases (DZNE)
Angelika Griep: German Center for Neurodegenerative Diseases (DZNE)
Francesco Santarelli: German Center for Neurodegenerative Diseases (DZNE)
Frederic Brosseron: German Center for Neurodegenerative Diseases (DZNE)
Sabine Opitz: University Hospital of Bonn
James Stunden: IFM Therapeutics GmbH
Maximilian Merten: University Hospital of Bonn
Rakez Kayed: University of Texas Medical Branch
Douglas T. Golenbock: University of Massachusetts Medical School
David Blum: University of Lille, Inserm, CHU-Lille, UMR-S 1172, “Alzheimer & Tauopathies”, Labex DISTALZ
Eicke Latz: German Center for Neurodegenerative Diseases (DZNE)
Luc Buée: University of Lille, Inserm, CHU-Lille, UMR-S 1172, “Alzheimer & Tauopathies”, Labex DISTALZ
Michael T. Heneka: University Hospital of Bonn

Nature, 2019, vol. 575, issue 7784, 669-673

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1769-z

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