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Nature. 2019 Nov;575(7784):669-673. doi: 10.1038/s41586-019-1769-z. Epub 2019 Nov 20.

NLRP3 inflammasome activation drives tau pathology.

Author information

1
Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany.
2
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
3
Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany.
4
IFM Therapeutics GmbH, Bonn, Germany.
5
Mitchell Center for Neurodegenerative Diseases and Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
6
Divison of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.
7
University of Lille, Inserm, CHU-Lille, UMR-S 1172, "Alzheimer & Tauopathies", Labex DISTALZ, Lille, France.
8
Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany. michael.heneka@ukbonn.de.
9
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. michael.heneka@ukbonn.de.
10
Divison of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA. michael.heneka@ukbonn.de.

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.

PMID:
31748742
DOI:
10.1038/s41586-019-1769-z

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