The NLRP3 inflammasome modulates tau pathology and neurodegeneration in a tauopathy model

An active role of neuroinflammation and the NLRP3 inflammasome in Alzheimer's disease and related tauopathies is increasingly identified, supporting NLRP3 as an interesting therapeutic target. However, its effect on tau‐associated neurodegeneration, a key‐process in tauopathies, remains unknown. While tau pathology and neurodegeneration are closely correlated, different tau forms may act as culprits in both characteristics and NLRP3‐dependent microglial processes may differently affect both processes, indicating the need to study the role of NLRP3 in both processes concomitantly. To study the role of NLRP3 on tau pathology, prion‐like propagation and tau‐associated neurodegeneration we generated crosses of NLRP3 deficient mice with tauP301S (PS19) transgenic mice. In this model we studied non‐seeded tau pathology and hippocampal atrophy, reminiscent characteristics of tauopathies. Tau pathology in hippocampus and cortex was significantly decreased in tau.NLRP3−/− versus tau.NLRP3+/+ mice. Importantly, tau.NLRP3−/− mice also displayed significantly decreased hippocampal atrophy, indicating a role of NLRP3 in neurodegeneration. We furthermore assessed the effect of NLRP3 deficiency on tau propagation and associated hippocampal atrophy. NLRP3 deficiency significantly decreased prion‐like seeding and propagation of tau pathology, reflected in decreased tau pathology in ipsi‐ and contralateral hippocampus and cortex in tau.NLRP3−/− following tau seeding. Most importantly, hippocampal atrophy was significantly less in tau‐seeded tau.NLRP3−/− mice at 8 months. We here demonstrate for the first time that NLRP3 activation affects tau‐associated neurodegeneration and seeded and non‐seeded tau pathology, hence affecting key molecular processes in tauopathies. Our data thereby provide key‐information in the validation of NLRP3 inflammasome as therapeutic target for AD and related tauopathies.