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Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice (Spatial Transcriptomics)

ABSTRACT: Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice (Spatial Transcriptomics)

PROVIDER: PRJNA1126288 | ENA |

REPOSITORIES: ENA

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Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice (Spatial Transcriptomics)

Project description:Unique microglial states have been identified in Alzheimer’s disease (AD) model mice and postmortem AD brains. Although it has been well documented that amyloid-β accumulation induces the alteration of microglial states, the relationship between tau pathology and microglial states remains incompletely understood because of a lack of suitable AD models. In the present study, we generated a novel AD model mouse by the intracerebral administration of tau purified from human brains with primary age-related tauopathy into AppNL-G-F/MAPT double knock-in (dKI) mice.

2024-12-16 | GSE270382 | GEO

Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice (snRNA-seq, part 2)

2024-12-16 | GSE270386 | GEO

Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice (snRNA-seq, part 1)

2024-12-16 | GSE270385 | GEO

Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice

Project description:Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice

| PRJNA1126281 | ENA

Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice (snRNA-seq, part 1)

Project description:Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice (snRNA-seq, part 1)

| PRJNA1126291 | ENA

Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice (snRNA-seq, part 2)

Project description:Tau accumulation induces microglial state alterations in Alzheimer’s disease model mice (snRNA-seq, part 2)

| PRJNA1126290 | ENA

Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [snRNA-Seq]

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

Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [bulk RNA-Seq]

2022-03-10 | GSE198013 | GEO

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα on tau pathology are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolic processes, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

2023-07-12 | GSE236875 | GEO

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα deletion in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deficient enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

2023-08-09 | PXD043877 | Pride

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