Proteopathic tau primes and activates interleukin-1β via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway

Jiang, Shanya; Maphis, Nicole; Binder, Jessica; Chisholm, Devon; Weston, Lea; Duran, W. A.; Peterson, Crina; Zimmerman, Amber; Mandell, Michael A.; Jett, Stephen D.; Bigio, Eileen H.; Geula, Changiz; Mellios, Nikolaos; Weick, Jason P.; Rosenberg, Gary A.; Latz, Eicke; Heneka, Michael T.; Bhaskar, Kiran

doi:10.1016/j.celrep.2021.109720

Cited by 53 publications

(53 citation statements)

References 85 publications

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“…We and others have previously demonstrated that tau and preaggregated tau activates the NLRP3-ASC inflammasome (Ising et al, 2019;Jiang et al, 2021;Stancu et al, 2019). We previously demonstrated a modulatory role of the NLRP3-ASC inflammasome on seeded and non-seeded tau pathology using ASC knockout and pharmacological NLRP3 inhibition in mice (Stancu et al, 2019).…”

Section: Discussionmentioning

confidence: 92%

“…It must be considered that different microglia‐dependent processes—in addition to neuronal characteristics—may contribute to modulation of tau pathology. NLRP3 inflammasome activation may contribute to tau pathology by (i) secretion of cytokines (including IL1β) which may affect tau phosphorylation (Bhaskar et al, 2010 ; Ghosh et al, 2013 ; Li et al, 2003 ; Maphis et al, 2015 ), by (ii) inducing ASC speck formation (Venegas et al, 2017 ), (iii) by phagocytosing tau (Ising et al, 2019 ; Jiang et al, 2021 ; Stancu et al, 2019 ) and by (iv) modifying proliferation/cell death/differentiation of microglial populations which can differentially contribute to tau pathology. The overall modulation of NLRP3 on tau pathology will be defined by the resultant effects of these different microglia‐dependent processes, which are modulated by NLRP3.…”

Section: Discussionmentioning

confidence: 99%

“…NLRP3 may affect tau‐associated neurodegeneration by modulating concentrations of tau forms intra‐ and extracellularly. Tau can be phagocytosed by microglia (Ising et al, 2019 ; Jiang et al, 2021 ; Stancu et al, 2019 ), but alternatively ASC specks similar as for Aβ may facilitate tau aggregation (Jiang et al, 2021 ; Venegas et al, 2017 ), and cytokines may increase phosphorylated tau forms intracellularly increasing toxic tau species (Bhaskar et al, 2010 ; Ghosh et al, 2013 ; Li et al, 2003 ; Maphis et al, 2015 ). Furthermore, microglial proliferation, differentiation and death can be modulated by NLRP3 activation induced by tau (Heneka et al, 2018 ), thereby shifting microglial functions and potentially their role in neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

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

Stancu

Lodder

Lucena

et al. 2022

Glia

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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.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Stancu

Lodder

Lucena

et al. 2022

Glia

View full text Add to dashboard Cite

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“…Mammalian targets that inhibit rapamycin complex 1 (mTORC1) can inhibit hexokinase 1-dependent glycolysis and caspase-1 activation, which indicates that inflammasome activation of NLRP3 is involved in macrophage metabolism [ 127 ]. Aβ [ 85 , 86 , 87 , 88 ] and tau [ 107 , 108 , 109 , 110 ] can activate NLRP3 of microglia via converting its metabolism into sugar [ 107 , 127 ]. Bradley L. Heckmann et al activated RAW264.7 and BMDM at Aβ is closely related to TREM2 and CD63 [ 128 ].…”

Section: Aβ and Tau As A Regulator Of Microglia Metabolism Reprogrammingmentioning

confidence: 99%

Aβ and Tau Regulate Microglia Metabolism via Exosomes in Alzheimer’s Disease

et al. 2022

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One of the most striking hallmarks shared by various neurodegenerative diseases, including Alzheimer’s disease (AD), is microglia-mediated neuroinflammation. The main pathological features of AD are extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles. The crosstalk between microglia and neurons helps maintain brain homeostasis, and the metabolic phenotype of microglia determines its polarizing phenotype. There are currently many research and development efforts to provide disease-modifying therapies for AD treatment. The main targets are Aβ and tau, but whether there is a causal relationship between neurodegenerative proteins, including Aβ oligomer and tau oligomer, and regulation of microglia metabolism in neuroinflammation is still controversial. Currently, the accumulation of Aβ and tau by exosomes or other means of propagation is proposed as a regulator in neurological disorders, leading to metabolic disorders of microglia that can play a key role in the regulation of immune cells. In this review, we propose that the accumulation of Aβ oligomer and tau oligomer can propagate to adjacent microglia through exosomes and change the neuroinflammatory microenvironment by microglia metabolic reprogramming. Clarifying the relationship between harmful proteins and microglia metabolism will help people to better understand the mechanism of crosstalk between neurons and microglia, and provide new ideas for the development of AD drugs.

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“…When we treated microglia with pathological tau with hyperphosphorylation and aggregation-containing neuronal media, exosomes, or paired-helical filaments from the human tauopathy brain, we observed interleukin-1β (IL-1β) activation, which is dependent on NLRP3, ASC, and caspase-1 ( Jiang et al., 2021 ). The pathological tau burden coexists with elevated IL-1β and ASC in autopsy brains of human tauopathies ( Jiang et al., 2021 ). Reduced ubiquitin-proteasome system activity has been found in patients affected by AD and its malfunction plays a significant role in Aβ accumulation ( Bellia et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%