Rho-associated kinases contribute to the regulation of tau phosphorylation and amyloid metabolism during neuronal plasticity

Background Neural plasticity under physiological condition develops together with normal tau phosphorylation and amyloid precursor protein (APP) processing. Since restoration of PI3-kinase signaling has therapeutic potential in Alzheimer's disease, we investigated plasticity-related changes in tau and APP metabolism by the selective Rho-kinase inhibitor fasudil. Methods Field potentials composed of a field excitatory post-synaptic potential (fEPSP) and a population spike (PS) were recorded from a granule cell layer of the dentate gyrus. Plasticity of synaptic strength and neuronal function was induced by strong tetanic stimulation (HFS) and low-frequency stimulation (LFS) patterns. Infusions of saline or fasudil were given for 1 h starting from the application of the induction protocols. Total and phosphorylated tau levels and soluble APP alpha levels were measured in the hippocampus, which was removed after at least 1 h post-induction period. Results Fasudil infusion resulted in attenuation of fEPSP slope and PS amplitude in response to both HFS and LFS. Fasudil reduced total tau and phosphorylated tau at residue Thr(181) in the HFS-stimulated hippocampus, while Thr(231) phosphorylation was reduced by fasudil treatment in the LFS-stimulated hippocampus. Ser(416) phosphorylation was increased by fasudil treatment in both HFS- and LFS-stimulated hippocampus. Fasudil significantly increased soluble APP alpha in LFS-stimulated hippocampus, but not in HFS-stimulated hippocampus. Conclusion In light of our findings, we suggest that increased activity of Rho kinase could trigger a mechanism that goes awry during synaptic plasticity which is reversed by a Rho-kinase inhibitor. Thus, Rho-kinase inhibition might be a therapeutic target in cognitive disorders.

Automated summary

The study showed that the Rho-kinase inhibitor fasudil can modulate tau and APP metabolism, thus regulating synaptic plasticity in the hippocampus. This suggests that inhibition of Rho-kinase could be a potential therapeutic target for cognitive disorders.