# Protein kinase CK2α’ as a dual modulator of neuroimmune signaling and synaptic dysfunction in Tauopathy

## TL;DR

This study identifies CK2α’ as a key driver of tau-related brain damage and suggests it could be a new target for treating tau-related diseases like Alzheimer's.

## Contribution

CK2α’ is shown as a novel regulator of tau pathology, neuroinflammation, and synaptic dysfunction in tauopathies.

## Key findings

- CK2α’ levels are elevated in the hippocampus of tauopathy mice and human dementia brains.
- Reducing CK2α’ lowers tau levels, improves synaptic function, and reduces inflammation in mice.
- CK2α’ depletion rescues cognitive deficits and alters immune signaling in tauopathy models.

## Abstract

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.

We used cell and mouse models to explore the impact of CK2α’ in tauopathy. We explored our hypothesis using molecular, biochemical, behavioral and electrophysiological techniques.

Here, we show CK2α’, one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. We found that CK2α’ expression is elevated in the hippocampus of PS19 tauopathy mice and in postmortem brains of dementia patients, particularly in neurons and microglia. Using genetic haploinsufficiency in PS19 mice, we demonstrated that reduced CK2α’ levels significantly decrease phosphorylated tau and total tau burden in the hippocampus and cortex. CK2α’ depletion also enhanced synaptic gene expression, synaptic density, and LTP, while attenuating microglial activation, synaptic engulfment, and pro-inflammatory cytokine levels. Importantly, CK2α’ depletion rescued cognitive deficits assessed in the Barnes maze. These effects appear to be mediated through both neuronal and glial functions and may involve CK2α’-dependent modulation of tau-associated phosphorylation and neuroinflammatory and immune signaling pathways.

Our findings highlight CK2α’ as a key node at the intersection of tau pathology, synaptic dysfunction, and neuroimmune signaling. Targeting CK2α’ may offer a novel and selective therapeutic strategy for modifying disease progression in tauopathies.