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Microbial infection instigates tau-related pathology in Alzheimer's disease via activating neuroimmune cGAS-STING pathway

ABSTRACT: Microbial infection instigates tau-related pathology in Alzheimer's disease via activating neuroimmune cGAS-STING pathway

PROVIDER: PRJNA1102867 | ENA |

REPOSITORIES: ENA

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	SRR28758451_1.fastq.gz	Fastqsanger.gz
	SRR28758451_2.fastq.gz	Fastqsanger.gz
	SRR28758453_1.fastq.gz	Fastqsanger.gz
	SRR28758453_2.fastq.gz	Fastqsanger.gz

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Microbial infection instigates tau-related pathology in Alzheimer's disease via activating neuroimmune cGAS-STING pathway

Project description:Microbial infection, the strong trigger to directly induce inflammation in brain, is long considered a risk factor of Alzheimer's disease (AD), but how these infections contribute to neurodegeneration remains underexplored. To examine the effect of herpes simplex virus type 1 (HSV-1) infection on tauopathy in local hippocampus of P301S mice, we utilized a modified HSV-1 strain (mHSV-1) potentially relevant to AD, we found that its infection promotes tau-related pathology in part via activating neuroimmune cGAS-STING pathway in the tau mouse model. Specifically, Sting ablation causes the detectable improvement of neuronal dysfunction and loss in P301S mice, which is causally linked to lowered proinflammatory status in the brain. Administration of STING inhibitor H-151 alleviates neuroinflammation and tau-related pathology in P301S mice. These results jointly suggest that herpesviral infection, as the vital environmental risk factor, could induce tau-related pathology in AD pathogenesis partially via neuroinflammatory cGAS-STING pathway.

2024-04-11 | GSE229411 | GEO

Microbial infection instigates tau-related pathology in Alzheimer's disease via activating neuroimmune cGAS-STING pathway

2025-04-17 | GSE264504 | GEO

Microbial infection instigates tau-related pathology in Alzheimer's disease via activating neuroimmune cGAS-STING pathway

Project description:Microbial infection instigates tau-related pathology in Alzheimer's disease via activating neuroimmune cGAS-STING pathway

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Immunometabolic dysregulation in microglia drives brain ageing via neuroimmune cGAS-STING

Project description:Immunometabolic dysregulation in microglia drives brain ageing via neuroimmune cGAS-STING

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Immunometabolic dysregulation in microglia drives brain ageing via neuroimmune cGAS-STING

Project description:Ageing and age-related brain disorders are typically concomitant with cellular mitochondrial dysfunction and metabolic dysregulation in immune cells. However, whether and how immunometabolic dysregulation in the brain affects neurological function are incompletely understood. Here we reveal the presence of metabolic dysregulation within microglia, the brain-resident immune cells, in aged mice. We discover that microglia with dysregulated immunometabolism, induced by dysfunctional mitochondria, initially act as triggers of brain ageing-related neurological dysfunctions in mice, which are mechanistically driven by microglial immunometabolic disturbance-induced inflammaging response depending on neuroimmune cGAS-STING pathway. We present evidence that a combined treatment targeting both metabolism and neuroinflammation partially rescues brain ageing in mice. These findings establish a causal link between immunometabolism, neuroimmunity, and brain ageing, underscoring the significance of tightly regulated immunometabolism in age-associated neurological diseases.

2025-04-28 | GSE266053 | GEO

cGAS Senses Translation Stress Through Direct Binding to Ribosomes

Project description:The cGAS-STING pathway, a central component of the innate immune system, senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to mediate inflammation. Here we report the unexpected discovery that cGAS senses dysfunctional protein production. Purified ribosomes interact with and stimulate the catalytic activity of recombinant cGAS in vitro. Disruption of the ribosome-associated protein quality control pathway, which detects and resolves ribosome collisions, results in cGAS- and STING-dependent ISG expression, and causes the re-localization of cGAS from the nucleus to the cytosol. Indeed, cGAS preferentially binds collided ribosomes in vitro, and other orthogonal perturbations that lead to elevated levels of collided ribosomes cause re-localization of cGAS as well. Thus, the cGAS-STING pathway senses and responds to translation stress. These findings have implications for the inflammatory responses to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.

2021-09-09 | PXD019359 | Pride

Transcriptome changes after the transfection of cGAS specific agonist G3-YSD

Project description:The cGAS-STING signalling has been well recognized as the major pathway response to self and non-self DNA molecule in cytoplasm. Here, we measured the temporal transcriptome dynamic changes after cGAS-STING signalling activation based on cGAS specific agonist G3-YSD transfection

2022-12-09 | GSE207458 | GEO

Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model

Project description:The strongest risk factors for Alzheimer’s disease (AD) include the 4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that the R47H variant induces neurodegeneration in 9- to- 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.

2024-08-22 | PXD053544 | Pride

Neddylation modification on cGAS of human and mouse

Project description:The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. We further identified Lys231 and Lys421 as the key neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.

2021-02-22 | PXD024088 | Pride

cGAS Senses Translation Stress Through Direct Binding to Ribosomes

Project description:The cGAS-STING pathway, a central component of the innate immune system, senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to mediate inflammation. Here we report the unexpected discovery that cGAS senses dysfunctional translation. Purified ribosomes interact with and stimulate recombinant cGAS catalytic activity in vitro. Disruption of the ribosome-associated protein quality control pathway, which detects and resolves ribosome collisions, results in cGAS- and STING-dependent ISG expression, and cause the re-localization of cGAS from the nucleus to the cytosol. Other orthogonal perturbations that lead to elevated levels of collided ribosomes cause re-localization of cGAS as well. Thus, the cGAS-STING pathway senses and responds to translation stress. These findings have implications for the inflammatory responses to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.

2020-05-26 | GSE151127 | GEO