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Updated: Oct 13, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation
Meihua Jin1, Hiroki Shiwaku2, Hikari Tanaka1
1Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Abstract:
Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders.
Insights
Polyglutamine binding protein 1 (PQBP1) acts as an intracellular sensor for tau proteins, initiating brain inflammation via the cGAS-STING pathway. This discovery reveals a shared mechanism between viral infections and neurodegenerative diseases.
Area of Science:
- Neuroimmunology
- Molecular mechanisms of neurodegeneration
- Innate immune response in the central nervous system
Background:
- Neuroinflammation is a key driver of neurodegenerative diseases.
- Microglia play a critical role in sensing and responding to pathological stimuli in the brain.
- The cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway is a crucial component of the innate immune system.
Purpose of the Study:
- To elucidate the role of polyglutamine binding protein 1 (PQBP1) in sensing tau proteins and initiating neuroinflammation.
- To investigate the involvement of the cGAS-STING pathway in tau-mediated brain inflammation.
- To characterize PQBP1 as a potential therapeutic target for neurodegenerative disorders.
Main Methods:
- Utilized tamoxifen-inducible, microglia-specific depletion of PQBP1 in vitro and in vivo mouse models.
- Investigated the interaction between PQBP1 and tau proteins.
- Analyzed the activation of the cGAS-STING pathway, NFκB translocation, and inflammatory gene expression.
Main Results:
- PQBP1 directly interacts with tau proteins (3R/4R) and triggers an innate immune response.
- PQBP1 is essential for tau-induced nuclear factor κB (NFκB) translocation and subsequent inflammatory gene transcription.
- Depletion of PQBP1 ameliorated brain inflammation and cognitive impairment in vivo.
- PQBP1 acts as an intracellular receptor for both viral cDNA and tau protein in the cGAS-STING pathway.
Conclusions:
- PQBP1 is a critical sensor of tau pathology in microglia, activating the cGAS-STING pathway to drive neuroinflammation.
- This study identifies a conserved inflammatory mechanism linking viral infections and neurodegenerative diseases.
- Targeting PQBP1 may offer a novel therapeutic strategy for mitigating brain inflammation in tauopathies.
