Protein kinase CK2 alpha prime as a dual modulator of immune signaling and synaptic dysfunction in Tauopathy

Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein Kinase CK2 has been previously associated with different aspects of tau pathology but genetic evidence for the contribution of CK2 to tauopathy remained lacking. Here, we show CK2, one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. We found that CK2 expression is elevated in postmortem brains of dementia patients and in the hippocampus of PS19 tauopathy mice, especially in neurons and microglia. Using genetic haploinsufficiency in PS19 mice, we demonstrated that reduced CK2 levels significantly decrease phosphorylated tau and total tau burden in the hippocampus and cortex. CK2 depletion also attenuated microglial activation, pro-inflammatory cytokine production, and microglia synaptic engulfment, enhanced synaptic gene expression, synaptic density, and LTP. Importantly, CK2 depletion rescued cognitive deficits assessed in the Barnes maze. These effects appear to be mediated through both neuronal and glial functions and may involve CK2-dependent modulation of tau-associated phosphorylation and neuroinflammatory and immune signaling pathways. One Sentence summaryThis study highlights CK2 as a key node at the intersection of tau pathology, synaptic dysfunction, and neuroimmune signaling.