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.
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