Activation of the Reelin/GSK-3β/p-Tau Signaling Pathway in the Hippocampus of Patients with Temporal Lobe Epilepsy

Juan Lin,1,2,* Xinyu Lin,1,* Yong-Juan Fu,1 Xuran Li,3 Xin Li,3 Yujiao Wang,1,4 Lihong Zhao,1 Shun Yu,3 Yue-Shan Piao1,5,6 1Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China; 2Department of Pathology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 3Department of Neurobiology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China; 4Department of Pathology, Shanxi Provincial People’s Hospital, Affiliated People’s Hospital of Shanxi Medical University, Taiyuan, 030012, People’s Republic of China; 5Clinical Research Center for Epilepsy, Capital Medical University, Beijing, 100053, People’s Republic of China; 6National Center for Neurological Disorders, Beijing, 100053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yue-Shan Piao, Email [email protected]; Shun Yu, Email [email protected]: In this study, we evaluated the presence of tau deposition and protein expression of Reelin/GSK-3β/p-Tau signaling pathway in the hippocampus of patients with temporal lobe epilepsy (TLE).Methods: A total of 37 cases of TLE with and without hippocampal sclerosis (HS) were selected histopathologically for our study with 5 autopsy cases as the control group. Immunohistochemistry and the histelide assay, a novel technique quantifying antigens in paraffin section, were used to confirm the distribution of protein within Reelin/GSK-3β/p-Tau signaling pathway and validate the expression of GSK-3β and AT8 (hyperphosphorylated tau) in this study.Results: Immunohistochemical staining for AT8 revealed punctate and filamentous positive expression in the CA1, CA2 and CA3 regions of the hippocampus with TLE under the ependyma, distributed in a band-like pattern. By contrast, the control group did not exhibit any immunopositivity. GSK-3β was strongly positive in the neuronal bodies, apical dendrites and axons in both groups of TLE, while all controls were negative. In addition, there was no significant difference in the immunohistochemical labelling of Reelin among all cases. The histelide assay indicated that the amounts of AT8 and GSK-3β were significantly increased in the two TLE groups (P < 0.05). Notably, there was a positive correlation between AT8 and GSK-3β in TLE without HS (P < 0.05).Conclusion: The present data indicates that phosphorylated tau protein and GSK-3β are activated in the hippocampus of patients with TLE, and this is the first study to examine relevant proteins with the histelide assay in paraffin samples of human tissue. We consider that the regulatory network of tau protein between the two groups may be similar but not identical.Significance: This study emphasized the Reelin/GSK-3β/p-Tau signaling pathway in TLE with a quantitative data of human tissues innovatively, revealing inspiration for mechanism exploration.Keywords: epilepsy, temporal lobe epilepsy, hippocampal sclerosis, Reelin, GSK-3β, p-Tau