Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo

Abstract

Brains of Alzheimer’s disease patients are characterized by the presence of amyloid plaques and neurofbrillary tangles, both invariably associated with neuroinfammation. A crucial role for NLRP3–ASC infammasome [NACHT, LRR and PYD domains-containing protein 3 (NLRP3)–Apoptosis-associated speck-like protein containing a CARD (ASC)] in amyloid-beta (Aβ)-induced microgliosis and Aβ pathology has been unequivocally identifed. Aβ aggregates activate NLRP3–ASC infammasome (Halle et al. in Nat Immunol 9:857–865, 2008) and conversely NLRP3–ASC infammasome activation exacerbates amyloid pathology in vivo (Heneka et al. in Nature 493:674–678, 2013), including by prion-like ASC-speck cross-seeding (Venegas et al. in Nature 552:355–361, 2017). However, the link between infammasome activation, as crucial sensor of innate immunity, and Tau remains unexplored. Here, we analyzed whether Tau aggregates acting as prion-like Tau seeds can activate NLRP3–ASC infammasome. We demonstrate that Tau seeds activate NLRP3–ASC-dependent infammasome in primary microglia, following microglial uptake and lysosomal sorting of Tau seeds. Next, we analyzed the role of infammasome activation in prion-like or templated seeding of Tau pathology and found signifcant inhibition of exogenously seeded Tau pathology by ASC defciency in Tau transgenic mice. We furthermore demonstrate that chronic intracerebral administration of the NLRP3 inhibitor, MCC950, inhibits exogenously seeded Tau pathology. Finally, ASC defciency also decreased nonexogenously seeded Tau pathology in Tau transgenic mice. Overall our fndings demonstrate that Tau-seeding competent, aggregated Tau activates the ASC infammasome through the NLRP3–ASC axis, and we demonstrate an exacerbating role of the NLRP3–ASC axis on exogenously and non-exogenously seeded Tau pathology in Tau mice in vivo. The NLRP3–ASC infammasome, which is an important sensor of innate immunity and intensively explored for its role in health and disease, hence presents as an interesting therapeutic approach to target three crucial pathogenetic processes in AD, including prionlike seeding of Tau pathology, Aβ pathology and neuroinfammation.