Brains of
Alzheimer's disease patients are characterized by the presence of
amyloid plaques and neurofibrillary tangles, both invariably associated with
neuroinflammation. A crucial role for NLRP3-ASC
inflammasome [
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 identified. Aβ aggregates activate NLRP3-ASC
inflammasome (Halle et al. in
Nat Immunol 9:857-865, 2008) and conversely NLRP3-ASC
inflammasome 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
inflammasome 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
inflammasome. We demonstrate that Tau seeds activate NLRP3-ASC-dependent
inflammasome in primary microglia, following microglial uptake and lysosomal sorting of Tau seeds. Next, we analyzed the role of
inflammasome activation in
prion-like or templated seeding of Tau pathology and found significant inhibition of exogenously seeded Tau pathology by ASC deficiency in Tau transgenic mice. We furthermore demonstrate that chronic intracerebral administration of the NLRP3 inhibitor,
MCC950, inhibits exogenously seeded Tau pathology. Finally, ASC deficiency also decreased non-exogenously seeded Tau pathology in Tau transgenic mice. Overall our findings demonstrate that Tau-seeding competent, aggregated Tau activates the ASC
inflammasome 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
inflammasome, 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
prion-like seeding of Tau pathology, Aβ pathology and
neuroinflammation.