Glial uptake of amyloid beta induces NLRP3 inflammasome formation via cathepsin-dependent degradation of NLRP10.

The NLRP3 inflammasome forms in response to a diverse range of stimuli and is responsible for the processing and release of interleukin-1β (IL-1β) from the immunocompetent cells of the brain. The pathological peptide of Alzheimer's disease, amyloid beta (Aβ), induces formation of the NLRP3 inflammasome in a manner dependent on the family of proteases, cathepsins; however, the pathway by which cathepsins induce formation of the inflammasome has not yet been elucidated. In this study, we show that Aβ treatment of primary rat glial cultures increases cathepsin activation in the cytosol, formation of the NLRP3 inflammasome, caspase 1 activation and IL-1β release. We also show that a second NOD-like protein, NLRP10, is found bound to apoptosis-associated speck-like protein under resting conditions; however, with Aβ treatment, both in vitro and in vivo, NLRP10 is decreased. Further to these data, we show that cathepsins are capable of degrading NLRP10 and that treatment of glial cultures with recombinant NLRP10 reduces Aβ-induced caspase 1 activation and IL-1β release. We propose that Aβ-induced cathepsin released into the cytosol degrades NLRP10, thus allowing dissociation of NLRP3 and formation of the inflammasome.