[en] 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.
Disciplines :
Neurology
Author, co-author :
Ising, Christina; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Venegas, Carmen; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany
Zhang, Shuangshuang; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Scheiblich, Hannah; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Schmidt, Susanne V; Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany
Vieira-Saecker, Ana; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Schwartz, Stephanie; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Albasset, Shadi; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
McManus, Róisín M; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Tejera, Dario; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Griep, Angelika; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Santarelli, Francesco; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Brosseron, Frederic; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Opitz, Sabine; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Merten, Maximilian; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany
Kayed, Rakez; Mitchell Center for Neurodegenerative Diseases and Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA
Golenbock, Douglas T; Divison of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
Blum, David; University of Lille, Inserm, CHU-Lille, UMR-S 1172, "Alzheimer & Tauopathies", Labex DISTALZ, Lille, France
Latz, Eicke; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany ; Divison of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
Buée, Luc; University of Lille, Inserm, CHU-Lille, UMR-S 1172, "Alzheimer & Tauopathies", Labex DISTALZ, Lille, France
HENEKA, Michael ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany. michael.heneka@ukbonn.de ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. michael.heneka@ukbonn.de ; Divison of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA. michael.heneka@ukbonn.de
Acknowledgements 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). We thank I. Rácz for help with obtaining approval by the local ethical committee for the animal experiments; P. Davies for providing the MC1 and PHF-1 antibodies; the DZNE light microscope facility (LMF) for providing microscopes and advice; and the DZNE Image and Data Analysis Facility (IDAF) for providing analysis computers, software and advice.
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