The <scp>NLRP3</scp> inflammasome modulates tau pathology and neurodegeneration in a tauopathy model

Stancu, Ilie-Cosmin; Lodder, Chritica; Lucena, Pablo Botella; Vanherle, Sarah; Ravé, Manuel Gutiérrez de; Terwel, Dick; Bottelbergs, Astrid; Dewachter, Ilse

doi:10.1002/glia.24160

Cited by 27 publications

(15 citation statements)

References 59 publications

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“…In a different study, it was discovered that tau hyperphosphorylation was decreased in the granular cell layer of the dentate gyrus, the CA1 cell body area, and the hippocampus [ 57 ]. Another study found similar results, with significantly less hippocampal atrophy in mice after tau [ 58 ]. Cleaved caspase-1 and ASC were found to be significantly more abundant in PD patients’ brains than in controls [ 59 ].…”

Section: Discussionsupporting

confidence: 56%

β-Hydroxybutyrate Regulates Activated Microglia to Alleviate Neurodegenerative Processes in Neurological Diseases: A Scoping Review

2023

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This scoping review aimed to summarise the effects of the ketone body β-hydroxybutyrate. The review details the revealed pathways and functional properties following its intervention in the context of neurodegenerative diseases. In this study, 5 research publications that met the inclusion and exclusion criteria were shortlisted. Following the intervention, we discovered a tendency of reduced inflammatory status in microglia, as evidenced by lower levels of pro-inflammatory mediators produced, reduced microgliosis in afflicted tissues, and enhanced cognitive functions in neurodegenerative models. We found that there is a significant overlap in the mechanism of action of b-hydroxybutyrate (BHB) via activation of the G-protein-Coupled Receptor 109A (GPR109a) receptor and deactivation of the inflammasome complex. Furthermore, although comparing outcomes can be challenging due to the heterogeneity in the study model, the results we have assembled here were consistent, giving us confidence in the intervention’s efficacy. We also discussed new studies where BHB is involved in various roles in regulating inflammation in microglia, allowing for fresh therapeutic targets against neurodegeneration. This brief review provides evidence to support the huge potential of BHB in the treatment of neurodegenerative illnesses.

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Section: Discussionsupporting

confidence: 56%

β-Hydroxybutyrate Regulates Activated Microglia to Alleviate Neurodegenerative Processes in Neurological Diseases: A Scoping Review

2023

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“…The levels of aggregated tau (Delta F%) were calculated using the ratios of the two emission signals (620 and 665 nm), according to the manufacturer formula. HTRF-tau aggregates values were previously shown to correlate with tau pathology in our tau model [ 50 ]. Measurements of Aβ42 and Aβ40 concentrations in brain were measured using the MSD VPLEX Plus Aβ Peptide Panel 1 (6E10) Kit (K15200G-1).…”

Section: Methodsmentioning

confidence: 93%

“…Tau aggregates concentrations in total brain homogenates were measured using the homogeneous time resolved fluorescence (HTRF) tau aggregation kit (6FTAUPEG; Cisbio, Perkin-Elmer, FR) according to previously validated protocols in our group, following the manufacturer protocol [ 50 ]. After incubation overnight of total brain homogenates of Tau transgenic mice with the anti-tau-d2 antibody and anti-tau-tb antibody at room temperature on a 384-well plate (Cisbio), the HTRF signals were measured with a TECAN Safire 2 microplate reader (Tecan Group Ltd., CH).…”

Section: Methodsmentioning

confidence: 99%

Blood-based Aβ42 increases in the earliest pre-pathological stage before decreasing with progressive amyloid pathology in preclinical models and human subjects: opening new avenues for prevention

et al. 2022

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Blood-based (BB) biomarkers for Aβ and tau can indicate pathological processes in the brain, in the early pathological, even pre-symptomatic stages in Alzheimer’s disease. However, the relation between BB biomarkers and AD-related processes in the brain in the earliest pre-pathology stage before amyloid pathology develops, and their relation with total brain concentrations of Aβ and tau, is poorly understood. This stage presents a critical window for the earliest prevention of AD. Preclinical models with well-defined temporal progression to robust amyloid and tau pathology provide a unique opportunity to study this relation and were used here to study the link between BB biomarkers with AD-related processes in pre- and pathological stages. We performed a cross-sectional study at different ages assessing the link between BB concentrations and AD-related processes in the brain. This was complemented with a longitudinal analysis and with analysis of age-related changes in a small cohort of human subjects. We found that BB-tau concentrations increased in serum, correlating with progressive development of tau pathology and with increasing tau aggregates and p-tau concentrations in brain in TauP301S mice (PS19) developing tauopathy. BB-Aβ42 concentrations in serum decreased between 4.5 and 9 months of age, correlating with the progressive development of robust amyloid pathology in APP/PS1 (5xFAD) mice, in line with previous findings. Most importantly, BB-Aβ42 concentrations significantly increased between 1.5 and 4.5 months, i.e., in the earliest pre-pathological stage, before robust amyloid pathology develops in the brain, indicating biphasic BB-Aβ42 dynamics. Furthermore, increasing BB-Aβ42 in the pre-pathological phase, strongly correlated with increasing Aβ42 concentrations in brain. Our subsequent longitudinal analysis of BB-Aβ42 in 5xFAD mice, confirmed biphasic BB-Aβ42, with an initial increase, before decreasing with progressive robust pathology. Furthermore, in human samples, BB-Aβ42 concentrations were significantly higher in old (> 60 years) compared to young (< 50 years) subjects, as well as to age-matched AD patients, further supporting age-dependent increase of Aβ42 concentrations in the earliest pre-pathological phase, before amyloid pathology. Also BB-Aβ40 concentrations were found to increase in the earliest pre-pathological phase both in preclinical models and human subjects, while subsequent significantly decreasing concentrations in the pathological phase were characteristic for BB-Aβ42. Together our data indicate that BB biomarkers reflect pathological processes in brain of preclinical models with amyloid and tau pathology, both in the pathological and pre-pathological phase. Our data indicate a biphasic pattern of BB-Aβ42 in preclinical models and a human cohort. And most importantly, we here show that BB-Aβ increased and correlated with increasing concentrations of Aβ in the brain, in the earliest pre-pathological stage in a preclinical model. Our data thereby identify a novel critical window for prevention, using BB-Aβ as marker for accumulating Aβ in the brain, in the earliest pre-pathological stage, opening new avenues for personalized early preventive strategies against AD, even before amyloid pathology develops.

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“…Recently, the role of NLRP3 inflammasome in tauopathy-induced neurodegeneration attracts extensive attention [24]. It was published that tauopathy (Tau hyperphosphorylation) and neurodegeneration (hippocampal atrophy) were decreased in the NLRP3deficient mice compared with wild type mice, implying its critical role [42]. However, how NLRP3 inflammasome modulates Tau phosphorylation is far from clear.…”

Section: Discussionmentioning

confidence: 99%

The Mechanism of TNF-α-Mediated Accumulation of Phosphorylated Tau Protein and Its Modulation by Propofol in Primary Mouse Hippocampal Neurons: Role of Mitophagy, NLRP3, and p62/Keap1/Nrf2 Pathway

Zhang

Song

Ding

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Neuroinflammation-induced phosphorylated Tau (p-Tau) deposition in central nervous system contributes to neurodegenerative disorders. Propofol possesses neuroprotective properties. We investigated its impacts on tumor necrosis factor-α (TNF-α)-mediated p-Tau deposition in neurons. Methods. Mouse hippocampal neurons were exposed to propofol followed by TNF-α. Cell viability, p-Tau, mitophagy, reactive oxygen species (ROS), NOD-like receptor protein 3 (NLRP3), antioxidant enzymes, and p62/Keap1/Nrf2 pathway were investigated. Results. TNF-α promoted p-Tau accumulation in a concentration- and time-dependent manner. TNF-α (20 ng/mL, 4 h) inhibited mitophagy while increased ROS accumulation and NLRP3 activation. It also induced glycogen synthase kinase-3β (GSK3β) while inhibited protein phosphatase 2A (PP2A) phosphorylation. All these effects were attenuated by 25 μM propofol. In addition, TNF-α-induced p-Tau accumulation was attenuated by ROS scavenger, NLRP3 inhibitor, GSK3β inhibitor, or PP2A activator. Besides, compared with control neurons, 100 μM propofol decreased p-Tau accumulation. It also decreased ROS and NLRP3 activation, modulated GSK3β/PP2A phosphorylation, leaving mitophagy unchanged. Further, 100 μM propofol induced p62 expression, reduced Keap1 expression, triggered the nuclear translocation of Nrf2, and upregulated superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) expression, which was abolished by p62 knockdown, Keap1 overexpression, or Nrf2 inhibitor. Consistently, the inhibitory effect of 100 μM propofol on ROS and p-Tau accumulation was mitigated by p62 knockdown, Keap1 overexpression, or Nrf2 inhibitor. Conclusions. In hippocampal neurons, TNF-α inhibited mitophagy, caused oxidative stress and NLRP3 activation, leading to GSK3β/PP2A-dependent Tau phosphorylation. Propofol may reduce p-Tau accumulation by reversing mitophagy and oxidative stress-related events. Besides, propofol may reduce p-Tau accumulation by modulating SOD and HO-1 expression through p62/Keap1/Nrf2 pathway.

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

Cited by 27 publications

References 59 publications

β-Hydroxybutyrate Regulates Activated Microglia to Alleviate Neurodegenerative Processes in Neurological Diseases: A Scoping Review

β-Hydroxybutyrate Regulates Activated Microglia to Alleviate Neurodegenerative Processes in Neurological Diseases: A Scoping Review

Blood-based Aβ42 increases in the earliest pre-pathological stage before decreasing with progressive amyloid pathology in preclinical models and human subjects: opening new avenues for prevention

The Mechanism of TNF-α-Mediated Accumulation of Phosphorylated Tau Protein and Its Modulation by Propofol in Primary Mouse Hippocampal Neurons: Role of Mitophagy, NLRP3, and p62/Keap1/Nrf2 Pathway

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