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NLRP3 inflammasome activation drives tau pathology

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.

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Fig. 1: NLRP3 inflammasome is activated in patients with FTD and Tau22 mice.
Fig. 2: Loss of NLRP3 inflammasome function decreases tau pathology and prevents cognitive decline.
Fig. 3: Nlrp3- and Asc-knockout inhibits CaMKII-α and promotes phosphatase activity.
Fig. 4: Inflammasome function is necessary for Aβ-induced tau pathology.

Data availability

All data generated and/or analysed during this study are either included in this article (and its Supplementary Information) or are available from the corresponding author on reasonable request. Source Data for Figs. 1–4 and Extended Data Figs. 1, 5–10 are provided with the paper.

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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.

Author information

Authors and Affiliations

Authors

Contributions

C.I. and M.T.H designed most of the experiments; C.I., C.V., S.Z. and H.S. performed experiments and analysed data with assistance of A.V.-S., A.G., F.S. and M.M.; D.T. quantified microglia morphology and performed ASC speck experiments; S.A. performed and analysed microglia treatments with tau; R.M.M. performed and analysed microbiome experiments; S.S. performed behaviour experiments; F.B. validated antibodies and helped with IL-1β analyses; S.O. provided neuron cultures; S.V.S and J.S. performed analysis of the NanoString data; M.T.H. quantified ASC specks and analysed data; R.K. provided tau oligomers; D.B., D.T.G., E.L. and L.B. provided mice, samples and advice; C.I. and M.T.H. wrote the manuscript with input from all co-authors.

Corresponding author

Correspondence to Michael T. Heneka.

Ethics declarations

Competing interests

E.L. is a co-founder and advisor, J.S. is an employee and M.T.H. serves as an advisory board member at IFM Therapeutics. M.T.H is an advisory board member at Alector. All other authors declare no competing interests.

Extended data figures and tables

Extended Data Fig. 1 The NLRP3 inflammasome is activated in Tau22 mice.

a, Immunoblot analysis of ASC and β-actin in human cortex of patients with FTD and control patients. b, Quantification of data from a. Box plots show 25th and 75th percentiles. n = 8 for controls, n = 9 for FTD, *P = 0.0239. c, Immunohistochemical staining of human cortex from a patient with FTD for microglia and ASC. n = 3. Scale bar, 20 μm. d, Quantification of percentage of intracellular ASC and of extracellular ASC specks from staining shown in Fig. 1g. n = 6 mice per group, ****P < 0.0001. e, Immunoblot analysis of hippocampus samples of 8-month-old wild-type and Tau22 mice stained for caspase-1 and β-actin. f, Quantification of data from e. n = 9 per group, *P = 0.0489. g, Immunoblot analysis of hippocampus samples of 8-month-old wild-type and Tau22 mice stained for IL-1β (p17) and β-actin. h, Quantification of data from g. n = 9 per group, *P = 0.0236. For gel source data, see Supplementary Fig. 1. All graphs are presented as mean ± s.e.m. and were analysed by two-tailed unpaired t-test.

Source Data

Extended Data Fig. 2 Gene signatures in wild-type and Tau22 mice identified by NanoString analysis.

a, Workflow for NanoString analysis. b, Two-dimensional principal component (PC) analysis of wild-type and Tau22 mice at 3, 8 and 11 months of age. c, Gene network analysis of regulated genes at 3 versus 8 months in wild-type and Tau22 mice identified by NanoString analysis. d, SOM clustering of wild-type and Tau22 mice at 3, 8 and 11 months of age with definition of gene sequences (i)–(vi). e, Gene signatures in 3-month-old Tau22 mice defined by cluster (iv) and in 11-month-old Tau22 mice defined by cluster (vi). Fisher’s exact test followed by a correction for multiple testing. f, Interferome Venn diagrams based on cluster (iv) and (vi) in Tau22 mice.

Extended Data Fig. 3 STRING network analysis of Tau22 mice.

a, b, Networks visualizing the functional protein association for gene signatures in Tau22 mice at 3 (a) and 11 (b) months of age. Nodes in the network represent proteins. Edges represent protein–protein interactions, which (depending on the colour) indicate known or predicted interactions.

Extended Data Fig. 4 Astrocyte morphology does not change in Tau22 mice.

a, Immunohistochemical staining for microglia (IBA1) and phosphorylated tau (AT8) in wild-type and Tau22 mice at 3 and 8 months of age. n = 8. Scale bar, 10μm. b, Immunohistochemical staining for astrocytes (GFAP) and phosphorylated tau (AT8) in wild-type and Tau22 mice at 3, 8 and 11 months of age. n = 8. Scale bar, 10 μm.

Extended Data Fig. 5 Knockout of Asc or Nlrp3 efficiently inhibits NLRP3 inflammasome function.

a, Immunoblot analysis of hippocampus samples from 11-month-old mice stained for caspase-1 and β-actin. b, Quantification of data from a. n = 6 for Tau22 and Tau22/Asc−/−, n = 9 for Tau22/Nlrp3−/−, *P = 0.0156, **P = 0.0012. c, Immunoblot analysis of hippocampus samples of 11-month-old mice stained for IL-1β (p17) and β-actin. d, Quantification of data from c. n = 7 for all groups. Tau22 versus Tau22/Asc−/−: *P = 0.0399, Tau22 versus Tau22/Nlrp3−/−: *P = 0.0310. e, Quantification of number of ASC specks/microglia, percentage of intracellular ASC specks and percentage of extracellular ASC specks in hippocampus sections of 11-month-old mice. n = 6 mice per group, ****P < 0.0001 for all comparisons. For gel source data, see Supplementary Fig. 1. All graphs are presented as mean ± s.e.m. and were analysed by one-way ANOVA followed by Tukey’s test.

Source Data

Extended Data Fig. 6 Tau pathology is reduced in inflammasome-knockout mice.

a, Immunohistochemical staining for phosphorylated tau (AT8) in mouse hippocampi. Scale bar, 500 μm. b, Quantification of AT8 in hippocampus, CA1 cell body layer and granular cell layer in the dentate gyrus of 3-month-old mice shown in a (n = 6 for hippocampus Tau22 and CA1 and dentate gyrus Tau22/Asc−/−, n = 4 for hippocampus Tau22/Asc−/− and dentate gyrus Tau22/Nlrp3−/−, n = 7 for hippocampus Tau22/Nlrp3−/− and CA1 and dentate gyrus Tau22, n = 5 for CA1 Tau22/Nlrp3−/−). *P = 0.0181. c, Quantification of AT8 in hippocampus, CA1 cell body layer and granular cell layer in the dentate gyrus of 8-month-old mice shown in a. Hippocampus: n = 12 for Tau22, n = 6 for Tau22/Asc−/−, n = 13 for Tau22/Nlrp3−/−. ***P = 0.0004 and ****P < 0.0001. CA1: n = 14 for Tau22, n = 8 for Tau22/Asc−/−, n = 15 for Tau22/Nlrp3−/−. Tau22 versus Tau22/Asc−/−: **P = 0.0052, Tau22 versus Tau22/Nlrp3−/−: ****P < 0.0001, Tau22/Asc−/− versus Tau22/Nlrp3−/−: **P = 0.0075. Dentate gyrus: n = 12 for Tau22, n = 6 for Tau22/Asc−/−, n = 13 for Tau22/Nlrp3−/−, ****P < 0.0001. d, Quantification of AT8 in granular cell layer in the dentate gyrus of 11-month-old mice shown in Fig. 2a. n = 17 for Tau22, n = 14 for Tau22/Asc−/−, n = 8 for Tau22/Nlrp3−/−, *P = 0.0196. e, Immunoblot analysis of sarkosyl-soluble fraction of hippocampi from 8-month-old Tau22, Tau22/Asc−/− and Tau22/Nlrp3−/− mice stained for misfolded tau (MC1), total tau (Tau5) and β-actin. f, Quantification of data from e. MC1: n = 12 for Tau22, n = 6 for Tau22/Asc−/−, n = 13 for Tau22/Nlrp3−/− with Tau22 versus Tau22/Nlrp3−/−: ***P = 0.0009 and Tau22/Asc−/− versus Tau22/Nlrp3−/−: *P = 0.0190. Human tau: n = 13 for Tau22, n = 7 for Tau22/Asc−/−, n = 14 for Tau22/Nlrp3−/−. Tau22 versus Tau22/Asc−/−: **P = 0.0047, Tau22 versus Tau22/Asc−/−: **P = 0.0037. g, Immunoblot detection of misfolded tau (MC1), total tau (Tau5) and β-actin in sarkosyl-soluble fraction of mouse hippocampi at 11 months of age. h, Quantification of data from g. n = 5, **P = 0.0056, ***P = 0.0001. For gel source data, see Supplementary Fig. 1. All graphs are presented as mean ± s.e.m. and were analysed by one-way ANOVA followed by Tukey’s test.

Source Data

Extended Data Fig. 7 Microglia and astrocyte numbers are unaltered in Tau22/Asc−/− and Tau22/Nlrp3−/− mice.

a, Immunohistochemical staining of hippocampus of mice with the indicated genotypes and at the indicated ages for microglia (IBA1). Scale bar, 250 μm. b, Quantification of IBA1-positive cells in the hippocampus as seen in a at 8 (left) and 11 months of age (right). n = 7 for 8 months wild-type, n = 6 for 11 months wild-type, n = 4 for 8 and 11 months Asc−/−, n = 5 for 8 and 11 months Nlrp3−/−, n = 11 for 8 and 11 months Tau22, n = 6 for 8 months Tau22/Asc−/−, n = 10 for 11 months Tau22/Asc−/−, n = 13 for 8 months Tau22/Nlrp3−/−, n = 6 for 11 months Tau22/Nlrp3−/−. c, Immunohistochemical staining of hippocampus of mice with the indicated genotypes and at the indicated ages for astrocytes (GFAP). Scale bar, 250 μm. d, Quantification of GFAP in the hippocampus as seen in c at 8 (left) and 11 months of age (right). n = 7 for 8 months wild-type, n = 6 for 11 months wild-type, n = 5 for 8 and 11 months Asc−/− and Nlrp3−/−, n = 11 for 8 months Tau22, n = 9 for 11 months Tau22, n = 6 for 8 months Tau22/Asc−/−, n = 11 for 11 months Tau22/Asc−/−, n = 13 for 8 months Tau22/Nlrp3−/−, n = 8 for 11 months Tau22/Nlrp3−/−. All graphs are presented as mean ± s.e.m. and were analysed by one-way ANOVA followed by Tukey’s test.

Source Data

Extended Data Fig. 8 Gene signatures in Tau22 and Tau22/Nlrp3−/− mice identified by NanoString analysis.

a, Two-dimensional PC analysis of Tau22 and Tau22/Nlrp3−/− mice at 3, 8 and 11 months of age. n = 5 independent samples for each group. b, Number of induced or suppressed genes comparing Tau22 versus Tau22/Nlrp3−/− at 3, 8 and 11 months. c, Gene plots of Tau22 versus Tau22/Nlrp3−/− at 3, 8 and 11 months. d, Heat map comparing significantly changed genes in Tau22 versus Tau22/Nlrp3−/− mice at various ages, identified by NanoString analysis.

Source Data

Extended Data Fig. 9 Nlrp3-knockout does not affect the microbiome of Tau22 mice.

a, Amount of bacteria in stool samples obtained from the colon of 11-month-old wild-type, Nlrp3−/−, Tau22 and Tau22/Nlrp3−/− mice. n = 6 for wild type, n = 4 for Nlrp3−/−, Tau22, Tau22/Nlrp3−/−. b, Caecum weight of 11-month-old wild-type, Nlrp3−/−, Tau22 and Tau22/Nlrp3−/− mice. n = 8 for wild type, n = 5 for Nlrp3−/−, n = 4 for Tau22, n = 6 for Tau22/Nlrp3−/−. c, Colon length of 11-month-old wild-type, Nlrp3−/−, Tau22 and Tau22/Nlrp3−/− mice. n = 8 for wild type, n = 5 for Nlrp3−/−, n = 4 for Tau22, n = 6 for Tau22/Nlrp3−/−, *P = 0.0350. df, IL-1β, IL-6 and TNF levels in colon samples of 11-month-old wild-type, Nlrp3−/−, Tau22 and Tau22/Nlrp3−/− mice. n = 8 for wild type, n = 4 for Nlrp3−/−, n = 5 for IL-1β and IL-6 in Tau22, n = 4 for TNF in Tau22, n = 6 for Tau22/Nlrp3−/−. gi, IL-1β, IL-6 and TNF levels in medial intestine samples of 11-month-old wild-type, Nlrp3−/−, Tau22 and Tau22/Nlrp3−/− mice. n = 8 for wild type, n = 4 for Nlrp3−/−, n = 4 for IL-1β in Tau22, n = 5 for IL-6 and TNF in Tau22, n = 6 for IL-1β and TNF in Tau22/Nlrp3−/−, n = 5 for IL-6 in Tau22/Nlrp3−/−. jl, IL-1β, IL-6 and TNF levels in spleen samples of 11-month-old wild-type, Nlrp3−/−, Tau22 and Tau22/Nlrp3−/− mice. n = 8 for wild type, n = 4 for Nlrp3−/−, n = 5 for Tau22, n = 6 for Tau22/Nlrp3−/−. mo, IL-1β, IL-6 and TNF levels in serum samples of 11-month-old wild-type, Nlrp3−/−, Tau22 and Tau22/Nlrp3−/− mice. n = 8 for wild type, n = 4 for Nlrp3−/− and Tau22, n = 6 for Tau22/Nlrp3−/−, *P = 0.0281. All graphs are presented as mean ± s.e.m. and were analysed by one-way ANOVA followed by Tukey’s test.

Source Data

Extended Data Fig. 10 Tau can activate the NLRP3 inflammasome.

a, Immunoblot analysis and quantification of total tau in primary neurons after treatment with conditioned medium from primary wild-type microglia (control), LPS/ATP-activated wild-type, Asc- or Nlrp3-knockout microglia (wild type + ATP, Asc–/– + ATP or Nlrp3–/– + ATP). n = 4 for each group. Control versus wild type + ATP: *P = 0.0252, wild type + ATP versus Asc–/– + ATP: *P = 0.0148, wild type + ATP versus Nlrp3–/– + ATP: **P = 0.0029. b, IL-1β levels in conditioned medium of primary wild-type microglia primed with LPS and treated with hippocampus homogenate from either 11-month-old wild-type or Tau22 mice. n = 5 for primed, n = 4 for wild-type and Tau22 homogenate treated microglia. Primed versus Tau22: **P = 0.0092, wild type versus Tau22: *P = 0.0276. c, IL-1β levels in conditioned medium of primary wild-type, Asc–/– and Nlrp3–/– microglia primed with LPS and treated with different forms of 2 μM recombinant wild-type tau (tau WT). n = 3 for Asc–/– and Nlrp3–/– microglia treatments and wild-type oligomer treatment, n = 8 for all other wild-type treatments. Wild-type primed versus wild-type monomers: **P = 0.0011, wild-type primed versus wild-type oligomers: ***P = 0.0007, wild-type monomers versus Asc–/– and Nlrp3–/– monomers: **P = 0.0011, wild-type monomers versus wild-type fibrils: *P = 0.0388, wild-type oligomers versus Asc–/– and Nlrp3–/– oligomers: ***P = 0.0004, wild-type oligomers versus wild-type fibrils: *P = 0.0112. d, IL-1β levels in conditioned medium of primary wild-type, Asc–/– and Nlrp3–/– microglia primed with LPS and treated with different forms of 2 μM recombinant tau with a P301S (tau P301S) mutation. n = 8 for wild-type microglia treatments, n = 3 for Asc–/– and Nlrp3–/– microglia treatments, ***P = 0.0002, **P = 0.0018. e, IL-1β levels in conditioned medium of primary wild-type microglia primed with LPS and treated with different forms of 2 μM recombinant tau wild type with and without the NLRP3 inhibitior CRID3. n = 4 for all groups, ***P = 0.0002, ****P < 0.0001. f, IL-1β levels in conditioned medium of primary wild-type microglia primed with LPS and treated with different forms of 2 μM recombinant tau P301S with and without CRID3 treatment. n = 4 for all groups, **P = 0.0037, ***P = 0.0005, ****P < 0.0001. g, Jess-based analysis of conditioned medium of LPS + tau wild-type-treated wild-type microglia stained for caspase-1. LPS/ATP-treated wild-type microglia served as positive control. h, Quantification of data from g. n = 7 for primed, n = 8 for tau monomers and fibrils, n = 4 for tau oligomers. *P = 0.0458, **P = 0.0091. i, Jess-based analysis of conditioned medium of primary wild-type, Asc–/– and Nlrp3–/– microglia primed with LPS and treated with the indicated forms of tau P301S. LPS/ATP-treated wild-type microglia served as positive control. Samples were stained for caspase-1. j, Quantification of data from i. n = 7 for primed and fibrils, n = 6 for monomers, *P = 0.0128. For gel source data, see Supplementary Fig. 1. All graphs are presented as mean ± s.e.m. and were analysed by one-way (a, b, h, j) or two-way ANOVA (cf) followed by Tukey’s test.

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Supplementary information

Supplementary Figure 1

The uncropped gels with size markers indicated

Reporting Summary

Supplementary Table 1

List of signature genes in WT and Tau22 mice identified by NanoString analysis. Genes underlying clusters as indicated in SOM clustering in Extended Data Fig. 2d. n=33 for cluster i. genes WT 3 months, n=58 for cluster ii. genes WT 8 months, n=39 for cluster iii. genes WT 11 months, n=168 for cluster iv. genes Tau22 3 months, n=33 for cluster v. genes Tau22 8 months, n=60 for cluster vi. genes Tau22 11 months

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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

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