Similar Datasets
Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy.
| S-EPMC9005658 | biostudies-literature
Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.
2022-03-10 | GSE198014 | GEO
Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.
2022-03-10 | GSE198013 | GEO
Project description:Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy
| PRJNA813402 | ENA
Project description:Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [snRNA-Seq]
| PRJNA813409 | ENA
Project description:Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [bulk RNA-Seq]
| PRJNA813410 | ENA
Project description:We aimed to investigate the influence of oligomeric forms of ?-amyloid (A?) and the influence of the duration of exposure on the development of tau phosphorylation.A? oligomers were injected intracranially either acutely into 5-month-old rTg4510 mice and tissue was collected 3 days later, or chronically into 3-month-old mice and tissue was collected 2 months later. Several forms of phosphorylated tau (p-tau), GSK3 (glycogen synthase kinase-3) and microglial and astrocyte activation were measured.Acute injections of A? oligomers had no effect on p-tau epitopes but did result in elevation of phosphorylated/activated GSK3 (pGSK3). Chronic infusion of A? oligomers into the right hippocampus resulted in 3- to 4-fold elevations in several p-tau isoforms with no changes in total tau levels. A significant elevation in pGSK3 accompanied these changes. Microglial staining with CD68 paralleled the increase in tau phosphorylation, however, CD45 staining was unaffected by A?. Control experiments revealed that the infusion of A? from the minipumps was largely complete by 10 days after implantation. Thus, the elevation in p-tau 2 months after implantation implies that the changes are quite persistent.Soluble A?(1-42) oligomers have long-lasting effects on tau phosphorylation in the rTg4510 model, possibly due to elevations in GSK3. These data suggest that even brief elevations in A? production, may have enduring impact on the risk for tauopathy.
| S-EPMC3739054 | biostudies-literature
Project description:Tau aggregation into ordered assemblies causes neurodegenerative tauopathies. We previously reported that tau monomer exists in either inert (Mi) or seed-competent (Ms) conformational ensembles and that Ms encodes strains, that is, unique, self-replicating, biologically active assemblies. It is unknown if disease begins with Ms formation followed by fibril assembly or if Ms derives from fibrils and is therefore an epiphenomenon. Here, we studied a tauopathy mouse model (PS19) that expresses full-length mutant human (1N4R) tau (P301S). Insoluble tau seeding activity appeared at 2 months of age and insoluble tau protein assemblies by immunoblot at 3 months. Tau monomer from mice aged 1 to 6 weeks, purified using size-exclusion chromatography, contained soluble seeding activity at 4 weeks, before insoluble material or larger assemblies were observed, with assemblies ranging from n = 1 to 3 tau units. By 5 to 6 weeks, large soluble assemblies had formed. This indicated that the first detectable pathological forms of tau were in fact Ms. We next examined posttranslational modifications of tau monomer from 1 to 6 weeks. We detected no phosphorylation unique to Ms in PS19 or human Alzheimer's disease brains. We conclude that tauopathy begins with formation of the Ms monomer, whose activity is phosphorylation independent. Ms then self assembles to form oligomers before it forms insoluble fibrils. The conversion of tau monomer from Mi to Ms thus constitutes the first detectable step in the initiation of tauopathy in this mouse model, with obvious implications for the origins of tauopathy in humans.
| S-EPMC9307951 | biostudies-literature
Project description:Alzheimer's disease is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell-derived microglia in both its free and extracellular vesicular-associated (EV-associated) forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the number of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in biogenesis of EVs. Single-cell RNA-Seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.
| S-EPMC10786694 | biostudies-literature
Project description:The intracerebral spread of tau is a critical mechanism associated with functional decline in Alzheimer's disease (AD) and other tauopathies. Recently, a hypothesis has emerged suggesting that tau propagation is linked to functional neuronal connections, specifically driven by neuronal hyperactivity. However, experimental validation of this hypothesis remains limited. In this study, we investigated how tau propagation from the entorhinal cortex to the hippocampus, the neuronal circuit most susceptible to tau pathology in AD, is affected by the selective stimulation of neuronal activity along this circuit. Using a mouse model of seed-induced propagation combined with optogenetics, we found that the chronic stimulation of this neuronal connection over a 4-week period resulted in a significant increase in insoluble tau accumulation in both the entorhinal cortex and hippocampus. Importantly, the ratio of tau accumulation in the hippocampus relative to that in the entorhinal cortex, serving as an indicator of transcellular spreading, was significantly higher in mice subjected to chronic stimulation. These results support the notion that abnormal neuronal activity promotes tau propagation, thereby implicating it in the progression of tauopathy.
| S-EPMC11354494 | biostudies-literature