Activation of NLRP3 inflammasome accelerates tau pathology

Abstract

Alzheimer’s disease (AD) is characterized by the extracellular accumulation of amyloid beta (Aβ), intraneuronal formation of neurofibrillary tangles composed of hyperphosphorylated tau, and activation of microglia, which are the innate immune cells of the brain. Aβ activates microglia to induce NLRP3, ASC and caspase-1 to assemble into the NLRP3 inflammasome. This complex stimulates the production and secretion of inflammatory mediators such as IL-1β and ASC specks. <br /> Here we investigated how the NLRP3 inflammasome contributes to the development and progression of tau pathology. Knockout of Asc or Nlrp3 from mice expressing human tau (“Tau22 mice”) reduced the activity of the tau kinases CaMKII and GSK-3β while promoting the activity of the tau phosphatase PP2A. This strongly protected mice from accumulation of hyperphosphorylated, misfolded tau. These protective effects were stronger in the absence of NLRP3 than in the absence of ASC. We confirmed these protective effects in vitro by incubating primary hippocampal neurons from Tau22 mice in conditioned medium from primary microglia that had been isolated from wild-type, Nlrp3^–/– or Asc^–/– mice and stimulated with LPS and ATP. Conditioned medium from microglia lacking NLRP3 or ASC led to less tau phosphorylation and accumulation as well as lower CaMKII activity in the hippocampal neurons. Inhibition of the IL-1 receptor or its downstream effectors IRAK4 or MEK1/2 protected the neurons from these effects. Injecting ASC specks directly into the hippocampus induced tau hyperphosphorylation and aggregation in Tau22 mice, but not Tau22/Asc^–/– or Tau22/Nlrp3^–/– mice. These results suggest that NLRP3 acts via IL-1β signaling to drive tau pathology and potentially also link tauopathy with Aβ pathology. <br /> This work supports the hypothesis that innate immune activation contributes to tau pathology. In Alzheimer’s disease, early Aβ deposition may induce NLRP3-mediated innate immune responses that lead to tau pathology and neuronal demise. Furthermore, this works shows that NLRP3 inflammasome activations also play a direct role in tauopathies independent of Aβ. In this way, the present work may help to develop new therapies against the disease.