Radiation-induced eCIRP Causes Alzheimer's Disease-like Neuronal Tau Phosphorylation

Area of Science:

• Neuroscience
• Radiology
• Pathology

Background:

• Cranial radiotherapy can cause neuroinflammation and cognitive deficits.
• Tau pathology is central to Alzheimer's disease (AD) but its role in radiation injury is unknown.
• Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel neuroinflammatory mediator implicated in tau hyperphosphorylation.

Purpose of the Study:

• To investigate if radiation promotes pathological tau phosphorylation via the eCIRP/IL6Rα/p25/Cdk5 pathway.
• To determine if the eCIRP inhibitor C23 can mitigate radiation-induced tau pathology.

Main Methods:

• Adult mice (C57BL/6 and CIRP-/-) were exposed to 10-Gy X-rays.
• Hippocampal tissues were analyzed for p25, phosphorylated tau, and CIRP via Western blotting.
• eCIRP and the inhibitor C23 were administered in vivo and in vitro.

Main Results:

• Irradiation significantly increased hippocampal p25, Cdk5 activity, and tau phosphorylation.
• CIRP levels increased in serum, CSF, and hippocampus post-irradiation.
• CIRP knockout mice showed reduced p25 and phosphorylated tau.
• eCIRP injection mimicked radiation effects on p25 and tau phosphorylation.
• C23 treatment attenuated radiation-induced increases in p25 and tau phosphorylation.

Conclusions:

• Radiation induces AD-like tau phosphorylation through the eCIRP/IL6Rα/p25/Cdk5 pathway.
• Targeting eCIRP with C23 effectively mitigates radiation-induced tau pathology.
• eCIRP is a novel mediator of neuroinflammation with significant implications for radiation-induced cognitive dysfunction and AD pathogenesis.