Activation of the NLRP3 inflammasome in microglia can drive tau pathology in a mouse model of frontotemporal dementia (FTD), according to a new study published in Nature. The findings also shed light on the role of microglia in Alzheimer disease (AD).

The NLRP3 inflammasome is a multiprotein complex consisting of NLRP3, ASC and caspase 1. The complex is assembled in activated microglia and induces release of the pro-inflammatory cytokine IL-1β. Evidence suggests that NLRP3 inflammasome activation is involved in the development of amyloid-β (Aβ) pathology in AD, but whether activity of this inflammasome also affects tau pathology is not clear. The new study aimed to address this uncertainty.

“Innate immune reactions occur in most neurodegenerative diseases, so we were interested in whether the NLRP3 signalling would be present in primary tauopathies,” explains Michael Heneka, who led the new study. Heneka and colleagues addressed this question in FTD, a neurodegenerative disease that is characterized by tau pathology, including neurofibrillary tangles.

The researchers analysed cortex samples from healthy individuals and individuals with FTD. Levels of ASC, mature IL-1β and cleaved caspase 1 were higher in FTD samples than in non-FTD samples, indicating activation of the NLRP3 inflammasome in the disease.

The researchers also analysed NLRP3 activation in the Tau22 mouse model of FTD. These mice overexpress mutated forms of human tau, and develop tau pathology and spatial memory deficits. NLRP3 activation in the brain was higher in Tau22 mice than in wild-type mice. Furthermore, ‘inflammasome knockout’ Tau22 mice, which were deficient in either ASC or NLRP3, had lower levels of tau pathology and did not show spatial memory deficits.

Finally, hippocampal injection of Aβ-containing brain homogenate induced tau pathology in Tau22 mice, but not in inflammasome-knockout Tau22 mice. This observation agrees with existing evidence that Aβ pathology induces tau pathology in AD and implicates the NLRP3 inflammasome in this process.

Innate immune reactions occur in most neurodegenerative diseases

“These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in AD, demonstrating that neurofibrillary tangles develop downstream of Aβ-induced microglial activation,” say the researchers in the paper.