NLRP3 deficiency led to a significant decrease in tau pathology and hippocampal atrophy in a mouse model of tauopathies.
Tau pathology in the hippocampus and cortex was significantly lower in NLRP3-deficient mice compared to those with normal NLRP3.
NLRP3 deficiency was associated with reduced hippocampal atrophy, suggesting a role of NLRP3 in neurodegeneration.
The absence of NLRP3 significantly decreased the prion-like seeding and propagation of tau pathology.
Decreased tau pathology was observed in the hippocampus and cortex following tau seeding in NLRP3-deficient mice.
Hippocampal atrophy at 8 months was significantly less in tau-seeded NLRP3-deficient mice.
Simplified
An active role of neuroinflammation and the 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.
Key numbers
significantly decreased
Decrease in Tau Pathology
Tau pathology in hippocampus and cortex in NLRP3 deficient mice.
significantly decreased
Decrease in Hippocampal Atrophy
Hippocampal atrophy in tau.NLRP3−/− vs. tau.NLRP3+/+ mice.
significantly decreased
Decrease in Tau Propagation
Prion-like propagation of tau pathology in NLRP3 deficient mice.
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