Nature 575, 669–673 (2019)

Frontotemporal dementia (FTD) is characterized by the aggregation of hyperphosphorylated tau protein in neurofibrillary tangles, neuroinflammation and cognitive loss. In Nature, Heneka and colleagues show that activation of the NLRP3 inflammasome regulates the hyperphosphorylation and aggregation of tau. Cleaved caspase-1, ASC and mature interleukin (IL-1β) are increased in cortex samples from patients with FTD and from old (8–11 months) Tau22 mice, which express the tau mutations associated with FTD. Tau22 Asc–/– and Tau22 Nlrp3–/– mice have less cleaved caspase-1, mature IL-1β and aggregated tau; less PP2A, GSK-3β and CamKII, which regulate the phosphorylation of tau; more neuroprotective CD300lf and ARC; and less spatial memory loss than Tau22 mice. Tau monomers and oligomers increase secretion of IL-1β in microglia, and injection of brain homogenates from APP/PS1 mice, a model of Alzheimer’s disease, induces the hyperphosphorylation of tau in Tau22 mice in a manner dependent on ASC and NLRP3.