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Neuroimmunology

Resilient brains run out of (c)GAS

Nature Immunology volume 24, pages 741–742 (2023)Cite this article

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New work from Udeochu, Amin, Huang, and colleagues provides mechanistic insights into how the tau protein engages the cGAS–STING pathway to elicit antiviral responses in Alzheimer’s disease. This signaling axis diminishes the MEF2C transcriptional network in neurons critical for maintaining cognitive function.

Alzheimer’s disease (AD), the most widespread cause of dementia, is characterized by the buildup of plaques and neurofibrillary tangles. Recently, the spotlight has been directed to immune responses associated with AD, as these can simultaneously be agents of damage and guardians of the brain1,2. The antiviral response typified by an elevation of type I interferons (IFN) is becoming increasingly recognized as a more prominent feature of AD3 and of aging, the greatest risk factor for AD. Nucleic acid sensors such as cyclic GMP-AMP synthase (cGAS) detect pathogenic or self-DNA in the context of stress and launch a signaling program through the stimulator of interferon genes (STING) to catalyze the expression of type I IFNs and other inflammatory mediators4. Although dysregulated type I IFN response has been associated with cognitive decline in aging5, how it arises through nucleic acid sensing has been largely unexplored in the context of AD. This important question, which holds therapeutic promise, was tackled in a new study in Nature Neuroscience by Udeochu et al.6.

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Fig. 1: A cGAS-dependent signaling cascade in microglia promotes downregulation of neuronal MEF2C and cognitive decline.

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Authors and Affiliations

  1. Brain Immunology and Glia (BIG) Center, Washington University in St. Louis, St. Louis, MO, USA

    Andrea Francesca M. Salvador & Jonathan Kipnis

  2. Department of Pathology and Immunology, Division of Immunobiology, Washington University in St. Louis, St. Louis, MO, USA

    Andrea Francesca M. Salvador & Jonathan Kipnis

  3. Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA

    Andrea Francesca M. Salvador

Authors
  1. Andrea Francesca M. Salvador
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  2. Jonathan Kipnis
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Correspondence to Jonathan Kipnis.

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Salvador, A.F.M., Kipnis, J. Resilient brains run out of (c)GAS. Nat Immunol 24, 741–742 (2023). https://doi.org/10.1038/s41590-023-01485-2

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