Ioana I. N. Da Silva; Daniel Ramírez; Sarah Parylak; Leslie A. Wallace; James K. Tucker; Joel M. Erberich; Rutvi Katariya; Aidan H. McDonald; Iryna S. Gallina; Ariana L. Tucker; Jillybeth Burgado; Baptiste N. Jaeger; Jerika J. Barron; Joshua M. Pratt; Monique Pena; Vipula Racha; Christina K. Lim; Sarah Fernandes; Simone K. Benassi; Lynne Randolph‐Moore; Krishna C. Vadodaria; Maria Carolina Marchetto; Nicola J. Allen; Fred H. Gage · 2026 · Nature Communications
Paper
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.
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Cuiying Fu; Heng Gu; Yan Dai; Xiaoke Dou; Yun Lin; Yangyang Ge
Yan Zhang; Peishen Han; Xiaoling Zhang
Margaux Océane Verdon; Vanessa Skipness; Lars Häusle; Natalia Barbara Pikor
Ramos AJ; Villarreal A
Gaitan AA; de Azevedo Pereira AV; Romero J; Lopez-Yunez A
Przywara D; Petniak A; Gil-Kulik P
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