German Center for Neurodegenerative Diseases (DZNE); University of Bonn - Institute of Innate Immunity; University of Massachusetts Worcester - Department of Medicine
University of Bonn - Institute of Innate Immunity; University of Massachusetts Worcester - Department of Medicine; University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry
Pathological 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 correlates with increased 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 tau tangles from human tauopathy brains 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.
Jiang, Shanya and Maphis, Nicole and Binder, Jessica and Chisholm, Devon and Weston, Lea and Duran, Walter and Floruta, Crina and Zimmerman, Amber and Jett, Stephen and Bigio, Eileen and Geula, Changiz and Mellios, Nikolaos and Weick, Jason and Latz, Eicke and Latz, Eicke and Heneka, Michael and Bhaskar, Kiran, Proteopathic Tau Primes and Activates Interleukin-1ß(Il-1ß) via MyD88- and NLRP3-ASC-Inflammasome Dependent Pathways (April 29, 2019). Available at SSRN: https://ssrn.com/abstract=3379896 or http://dx.doi.org/10.2139/ssrn.3379896
This version of the paper has not been formally peer reviewed.
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