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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE198013 | GEO | 2022/03/10

REPOSITORIES: GEO

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Project description:Background: Activation of microglia, the resident immune cells of the central nervous system, is a prominent pathological hallmark of Alzheimer’s disease (AD). However, the gene expression changes underlying microglia activation in response to tau pathology remain elusive. Furthermore, it is not clear how murine gene expression changes relate to human gene expression networks. Methods: Microglia cells were isolated from rTg4510 tau transgenic mice and gene expression was profiled using RNA sequencing. Four age groups of mice (2-, 4-, 6-, and 8-months) were analyzed to capture longitudinal gene expression changes that correspond to varying levels of pathology, from minimal tau accumulation to massive neuronal loss. Statistical and system biology approaches were used to analyze the genes and pathways that underlie microglia activation. Differentially expressed genes were compared to human brain co-expression networks. Results:Statistical analysis of RNAseq data indicated that more than 4000 genes were differentially expressed in rTg4510 microglia compared to wild type microglia, with the majority of gene expression changes occurring between 2- and 4-months of age. These genes belong to four major clusters based on their temporal expression pattern. Genes involved in innate immunity were continuously up-regulated, whereas genes involved in the glutamatergic synapse were down-regulated. Up-regulated innate inflammatory pathways included NF-κB signaling, cytokine-cytokine receptor interaction, lysosome, oxidative phosphorylation, and phagosome. NF-κB and cytokine signaling were among the earliest pathways activated, likely driven by the RELA, STAT1 and STAT6 transcription factors. The expression of many AD associated genes such as APOE and TREM2 was also altered in rTg4510 microglia cells. Differentially expressed genes in rTg4510 microglia were enriched in human neurodegenerative disease associated pathways, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, and highly overlapped with the microglia and endothelial modules of human brain transcriptional co-expression networks. Conclusion: This study revealed temporal transcriptome alterations in microglia cells in response to pathological tau perturbation and provides insights into the molecular changes underlying microglia activation during tau mediated neurodegeneration.

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

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