Journal Article

CK2 inhibition suppresses glial inflammation in models of neuroinflammation and neurodegeneration

Da Silva, Ioana I. N., Jaeger, Baptiste N., Vadodaria, Krishna C., Parylak, Sarah L., Burgado, Jillybeth, Benassi, Simone, Ramirez, Desiree, Katariya, Rutvi, Barron, Jerika J., Marchetto, Maria C., Gage, Fred H., Erberich, Joel M., Tucker, Ariana L., Fernandes, Sarah, Gallina, Iryna S., Pratt, Joshua M., Lim, Christina K., Tucker, James K., Pena, Monique, Wallace, Leslie A., Racha, Vipula, McDonald, Aidan H., Randolph-Moore, Lynne, Allen, Nicola J.

2026

Overview

Neuroinflammation plays a key role in Alzheimer’s disease (AD) and many other neurodegenerative disorders. Chronic activation of astrocytes and microglia fuels neuronal damage via cytokine secretion, oxidative stress, and proteolysis, yet glial inflammatory regulation remains poorly understood. Using chemoproteomics, we identified CK2, particularly the brain-enriched catalytic subunit CK2α2, as a key driver of astrocytic inflammation. CK2 enhances NF-κB activity by phosphorylating NF-κB S529 and IκBα S32, promoting pro-inflammatory gene expression. Genetic or chemical CK2 inhibition dampens inflammation, including IL-6 and IL-8 expression in a TNFα acute neuroinflammation mouse model. CK2α2 is upregulated in AD postmortem tissues and patient-derived astrocytes. AD astrocytes exhibit a hyperinflammatory state that can be attenuated by CK2 inhibition. Overexpression of CK2α2 in cortical organoids mimics AD pathology, whereas CK2 inhibition using the potent, selective, and brain-penetrant probe TAL606 rescues inflammatory markers in AD APP/PS1 mice. These findings position CK2 as a central regulator of neuroinflammation and a promising therapeutic target for AD and related disorders. Chemoproteomics coupled with patient-derived and organoid models identify and validate brain-enriched CK2α2 as an inflammatory driver in Alzheimer's disease. Blocking CK2 (including with brain-penetrant TAL606) lowers inflammatory signals in AD mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/100 / 13/106 / 13/109 / 13/31 / 13/51 / 13/89 / 38 / 38/91 / 631/154/1435 / 631/378/1689/364 / 631/378/340 / 82/1 / 96/47 / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Animal models / Animals / Astrocytes / Astrocytes - drug effects / Astrocytes - metabolism / Astrocytes - pathology / Brain / Brain - pathology / Casein Kinase II - antagonists & inhibitors / Casein Kinase II - genetics / Casein Kinase II - metabolism / Cytokines / Disease Models, Animal / E coli / Experiments / Female / Flavonoids / Flow cytometry / Gene expression / Humanities and Social Sciences / Humans / Inflammation / Kinases / Male / Mice / Mice, Transgenic / Microglia / Microglia - drug effects / Microglia - metabolism / multidisciplinary / Natural products / Neurodegeneration / Neurodegenerative Diseases / Neuroglia - drug effects / Neuroglia - metabolism / Neuroinflammatory Diseases - drug therapy / Neuroinflammatory Diseases - genetics / Neuroinflammatory Diseases - metabolism / Neuroinflammatory Diseases - pathology / Neuronal-glial interactions / NF-kappa B - metabolism / NF-κB protein / Organoids / Oxidative stress / Presenilin 1 / Proteins / Proteolysis / Science / Science (multidisciplinary) / Therapeutic targets