Proteopathic tau primes and activates interleukin-1ß (IL-1ß) via MyD88- and NLRP3-ASC-inflammasome dependent pathways cell-autonomous to microglia

Authors

• Shanya Jiang, Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
• Nicole M. Maphis, Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
• Jessica Binder, Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
• Devon Chisholm, Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
• Lea Weston, Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
• Walter Duran, Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
• Crina Floruta, Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
• Amber Zimmerman, Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
• Michael Mandell, Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA
• Stephen Jett, Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
• Eileen Bigio, Northwestern Cognitive Neurology & Alzheimer’s Disease Center (CNADC), Northwestern University, Chicago, IL 60611, USA
• Changiz Geula, Northwestern Cognitive Neurology & Alzheimer’s Disease Center (CNADC), Northwestern University, Chicago, IL 60611, USA
• Nikolaos Mellios, Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
• Jason Weick, Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
• Eicke Latz, Institute of Innate Immunity, University of Bonn, Bonn 53127, Germany; Department of Medicine, University of Massachusetts, Worcester, MA 01605, USA
• Michael Heneka, 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
• Kiran Bhaskar, Department of Molecular Genetics and Microbiology and Department of Neurology, University of New Mexico, Albuquerque, NM 87131, USA

Document Type

Poster

Publication Date

2021

Abstract

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-1ß. First, pTau burden co-exist with elevated IL-1β and inflammasome proteins (NLRP3 and ASC) in autopsy brains of human tauopathies. Suppression of human tau blocks both priming and activation of ASC and NLRP3 in the rTg4510 mouse model of tauopathy. Treating microglia with pTau-containing neuronal media, exosomes or purified human tau tangles causes IL-1β activation, which is NLRP3, ASC, and caspase-1-dependent.

While the microglia-restricted deletion of a common innate immune adaptor protein, MyD88 prevents both IL-1β expression and activation in the hTau mouse model of tauopathy, genetic deficiency of ASC within microglia reduces pTau-induced IL-1β activation and improves cognitive function in the hTau mice. Together, our results suggest that pTau activates IL-1β via MyD88- and NLRP3-ASC-dependent pathways and lead to neuroinflammation in tauopathies.

Comments

Poster presented at the Brain & Behavioral Health Research Day 2021

Recommended Citation

Jiang, Shanya; Nicole M. Maphis; Jessica Binder; Devon Chisholm; Lea Weston; Walter Duran; Crina Floruta; Amber Zimmerman; Michael Mandell; Stephen Jett; Eileen Bigio; Changiz Geula; Nikolaos Mellios; Jason Weick; Eicke Latz; Michael Heneka; and Kiran Bhaskar. "Proteopathic tau primes and activates interleukin-1ß (IL-1ß) via MyD88- and NLRP3-ASC-inflammasome dependent pathways cell-autonomous to microglia." (2021). https://digitalrepository.unm.edu/hsc-bbhrd/32