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

ABSTRACT: 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.

SUBMITTER: Stancu IC

PROVIDER: S-EPMC9307007 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

Project description:Brains of Alzheimer's disease patients are characterized by the presence of amyloid plaques and neurofibrillary tangles, both invariably associated with neuroinflammation. A crucial role for NLRP3-ASC inflammasome [NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-Apoptosis-associated speck-like protein containing a CARD (ASC)] in amyloid-beta (Aβ)-induced microgliosis and Aβ pathology has been unequivocally identified. Aβ aggregates activate NLRP3-ASC inflammasome (Halle et al. in Nat Immunol 9:857-865, 2008) and conversely NLRP3-ASC inflammasome activation exacerbates amyloid pathology in vivo (Heneka et al. in Nature 493:674-678, 2013), including by prion-like ASC-speck cross-seeding (Venegas et al. in Nature 552:355-361, 2017). However, the link between inflammasome activation, as crucial sensor of innate immunity, and Tau remains unexplored. Here, we analyzed whether Tau aggregates acting as prion-like Tau seeds can activate NLRP3-ASC inflammasome. We demonstrate that Tau seeds activate NLRP3-ASC-dependent inflammasome in primary microglia, following microglial uptake and lysosomal sorting of Tau seeds. Next, we analyzed the role of inflammasome activation in prion-like or templated seeding of Tau pathology and found significant inhibition of exogenously seeded Tau pathology by ASC deficiency in Tau transgenic mice. We furthermore demonstrate that chronic intracerebral administration of the NLRP3 inhibitor, MCC950, inhibits exogenously seeded Tau pathology. Finally, ASC deficiency also decreased non-exogenously seeded Tau pathology in Tau transgenic mice. Overall our findings demonstrate that Tau-seeding competent, aggregated Tau activates the ASC inflammasome through the NLRP3-ASC axis, and we demonstrate an exacerbating role of the NLRP3-ASC axis on exogenously and non-exogenously seeded Tau pathology in Tau mice in vivo. The NLRP3-ASC inflammasome, which is an important sensor of innate immunity and intensively explored for its role in health and disease, hence presents as an interesting therapeutic approach to target three crucial pathogenetic processes in AD, including prion-like seeding of Tau pathology, Aβ pathology and neuroinflammation.

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

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