Physiology Department of the Medical Faculty, Erciyes University, 38039, Kayseri, Turkey.
Pharmacol Rep. 2021 Oct;73(5):1303-1314. doi: 10.1007/s43440-021-00279-3. Epub 2021 Jun 1.
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.
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 APPα levels were measured in the hippocampus, which was removed after at least 1 h post-induction period.
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 in the HFS-stimulated hippocampus, while Thr phosphorylation was reduced by fasudil treatment in the LFS-stimulated hippocampus. Ser phosphorylation was increased by fasudil treatment in both HFS- and LFS-stimulated hippocampus. Fasudil significantly increased soluble APPα in LFS-stimulated hippocampus, but not in HFS-stimulated hippocampus.
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.
在生理条件下，神经可塑性与正常的 tau 磷酸化和淀粉样前体蛋白（APP）处理一起发展。由于恢复 PI3-激酶信号在阿尔茨海默病中有治疗潜力，我们研究了选择性 Rho 激酶抑制剂法舒地尔对 tau 和 APP 代谢的可塑性相关变化。
从齿状回颗粒细胞层记录由场兴奋性突触后电位（fEPSP）和群体锋电位（PS）组成的场电位。通过强强直刺激（HFS）和低频刺激（LFS）模式诱导突触强度和神经元功能的可塑性。在诱导方案应用后至少 1 小时开始，用生理盐水或法舒地尔进行 1 小时的输注。在诱导后至少 1 小时后取出海马体，测量总 tau 和磷酸化 tau 水平和可溶性 APPα 水平。
法舒地尔输注导致对 HFS 和 LFS 的 fEPSP 斜率和 PS 幅度的衰减。法舒地尔降低了 HFS 刺激海马体中的总 tau 和磷酸化 tau 在残基 Thr 的水平，而 LFS 刺激海马体中的 Thr 磷酸化被法舒地尔处理降低。Ser 磷酸化在 HFS 和 LFS 刺激的海马体中均被法舒地尔处理增加。法舒地尔在 LFS 刺激的海马体中显著增加可溶性 APPα，但在 HFS 刺激的海马体中没有增加。
鉴于我们的发现，我们建议 Rho 激酶活性的增加可能会触发突触可塑性过程中出现问题的机制，而 Rho 激酶抑制剂可逆转该机制。因此，Rho 激酶抑制可能是认知障碍的治疗靶点。
