[en] Pathological hyperphosphorylation and aggregation of tau (pTau) and neuroinflammation, driven by interleukin-1β (IL-1β), are the major hallmarks of tauopathies. Here, we show that pTau primes and activates IL-1β. First, RNA-sequence analysis suggests paired-helical filaments (PHFs) from human tauopathy brain primes nuclear factor κB (NF-κB), chemokine, and IL-1β signaling clusters in human primary microglia. Treating microglia with pTau-containing neuronal media, exosomes, or PHFs causes IL-1β activation, which is NLRP3, ASC, and caspase-1 dependent. Suppression of pTau or ASC reduces tau pathology and inflammasome activation in rTg4510 and hTau mice, respectively. Although the deletion of MyD88 prevents both IL-1β expression and activation in the hTau mouse model of tauopathy, ASC deficiency in myeloid cells reduces pTau-induced IL-1β activation and improves cognitive function in hTau mice. Finally, pTau burden co-exists with elevated IL-1β and ASC in autopsy brains of human tauopathies. Together, our results suggest pTau activates IL-1β via MyD88- and NLRP3-ASC-dependent pathways in myeloid cells, including microglia.
Disciplines :
Neurology
Author, co-author :
Jiang, Shanya; Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Maphis, Nicole M; Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Binder, Jessica; Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Chisholm, Devon; Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Weston, Lea; Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Duran, Walter; Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Peterson, Crina; Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
Zimmerman, Amber; Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
Mandell, Michael A; Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
Jett, Stephen D; Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
Bigio, Eileen; Cognitive Neurology and Alzheimer's Disease Center (CNADC), Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
Geula, Changiz; Cognitive Neurology and Alzheimer's Disease Center (CNADC), Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
Mellios, Nikolaos; Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
Weick, Jason P; Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
Rosenberg, Gary A; Center for Memory and Aging, University of New Mexico, Albuquerque, NM 87131, USA
Latz, Eicke; Institute of Innate Immunity, University of Bonn, Bonn 53127, Germany, Department of Medicine, University of Massachusetts, Worcester, MA 01605, USA
HENEKA, Michael ; Institute of Innate Immunity, University of Bonn, Bonn 53127, Germany, Department of Medicine, University of Massachusetts, Worcester, MA 01605, USA, Department of Neurodegenerative Disease and Gerontopsychiatry, University of Bonn, Bonn 53127, Germany
Bhaskar, Kiran; Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA, Department of Neurology, University of New Mexico, Albuquerque, NM 87131, USA. Electronic address: kbhaskar@salud.unm.edu
We thank Dr. Vishwa Dixit (Genentech) and Dr. Vojo Deretic (UNM) for providing ASC −/− mice and various reagents, respectively. We thank Drs. Xiaoxia Li and Zizhen Kang (Cleveland Clinic) for providing CD11bCre/MyD88 flox mice. We thank Dr. Amir Yazdi (University of Lausanne) for providing ASC flox mice. We are thankful to Dr. Michael Paffett at the UNM Cancer Center Fluorescence Microscopy facility and CTSC T1 lab for help with confocal imaging and RNA quantification, respectively. We thank Dr. Paulus Mrass for his assistance in processing live image files. We thank Dr. Bryce Chackerian, Ms. Julianne Peabody, Mr. Jeff Thompson, and Ms. Sasha Hobson for assistance with tau immunization experiments and analyzing tau levels in the CSF samples. The graphical abstract was created with https://www.biorender.com . This study was supported by the NIH ( RF1NS083704-05A1 , R01NS083704 , and R21NS077089 ; R21NS093442 to K.B.; and R01NS116051 to J.P.W.), AIM CoBRE Center ( P20GM121176-04 ), the University of New Mexico (UNM) Health Sciences Center Bridge Funding , UNM Department of Molecular Genetics and Microbiology intradepartmental grant funding, Dr. Stephanie Ruby travel award (to N.M. and J.B.), and a T32 training grant (to L.W.). This study was also supported in part by Alzheimer’s Disease Core Center ( P30AG013854 ) from the National Institute on Aging (NIA) to Northwestern University and New Mexico Alzheimer’s Disease Research Center ( P20AG068077-01 ) from NIA to G.A.R. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.We thank Dr. Vishwa Dixit (Genentech) and Dr. Vojo Deretic (UNM) for providing ASC−/− mice and various reagents, respectively. We thank Drs. Xiaoxia Li and Zizhen Kang (Cleveland Clinic) for providing CD11bCre/MyD88 flox mice. We thank Dr. Amir Yazdi (University of Lausanne) for providing ASC flox mice. We are thankful to Dr. Michael Paffett at the UNM Cancer Center Fluorescence Microscopy facility and CTSC T1 lab for help with confocal imaging and RNA quantification, respectively. We thank Dr. Paulus Mrass for his assistance in processing live image files. We thank Dr. Bryce Chackerian, Ms. Julianne Peabody, Mr. Jeff Thompson, and Ms. Sasha Hobson for assistance with tau immunization experiments and analyzing tau levels in the CSF samples. The graphical abstract was created with https://www.biorender.com. This study was supported by the NIH (RF1NS083704-05A1, R01NS083704, and R21NS077089; R21NS093442 to K.B.; and R01NS116051 to J.P.W.), AIM CoBRE Center (P20GM121176-04), the University of New Mexico (UNM) Health Sciences Center Bridge Funding, UNM Department of Molecular Genetics and Microbiology intradepartmental grant funding, Dr. Stephanie Ruby travel award (to N.M. and J.B.), and a T32 training grant (to L.W.). This study was also supported in part by Alzheimer's Disease Core Center (P30AG013854) from the National Institute on Aging (NIA) to Northwestern University and New Mexico Alzheimer's Disease Research Center (P20AG068077-01) from NIA to G.A.R. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. K.B. and S.J designed experiments. S.J performed majority of the experiments. J.P.W. E.L. and M.T.H. helped with conceptual planning and assisted with manuscript preparation. S.J. C.P. A.Z. and N.M. performed RNA-seq analysis and assisted with interpretations. S.J. L.W. N.M.M. and D.C. generated the mice and performed various biochemical analysis. J.B. performed exosome experiments. W.D. assisted in cell-culture experiments with S.J. and J.B. S.D.J. performed immune electron microscopy. E.B. and C.G. provided human autopsy brain samples. G.A.R. provided CSF. E.B. C.G. and G.A.R. assisted with manuscript preparation. M.A.M. performed NF-κB in vitro experiments. K.B. wrote the manuscript. The authors declare no competing interests.
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