Berberine Alleviates Tau Hyperphosphorylation and Axonopathy-Associated with Diabetic Encephalopathy via Restoring PI3K/Akt/GSK3β Pathway

Article type: Research Article

Authors: Wang, Shanshan^a | He, Benhong^d | Hang, Weijian^a | Wu, NingHua^f | Xia, Liangtao^a | Wang, Xu^a | Zhang, Qianying^a | Zhou, Xinwen^{b; c} | Feng, Zuohua^a | Chen, Qingjie^{a; e; *} | Chen, Juan^{a; b; c; *}

Affiliations: [a] Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China | [b] Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei, China | [c] Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China | [d] Department of Cardiovascular Medicine, Lichuan People’s Hospital, Lichuan, Hubei, China | [e] New products of TCM Senile Diseases Co-Innovation Center of Hubei, Basic Medical Sciences College, Hubei University of Chinese Medicine, Wuhan, Hubei, China | [f] Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, Hubei, China

Correspondence: [*] Correspondence to: Juan Chen and Qingjie Chen, Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. E-mail: [email protected] (J. Chen); E-mail: [email protected]. (Q. Chen)

Abstract: Background:Axonopathy is closely linked to the development of diabetic encephalopathy induced by type II diabetes (T2D). Berberine has been shown to cross the blood-brain barrier and holds promising effect for neuronal damage in diabetes. Objective:The present study investigated the protective effect and the underlying mechanism of berberine on neuronal axonopathy in both in vitro and in vivo models. Methods:High glucose/high fat diet and streptozotocin injection-induced T2D rat model was used. Berberine was administered p.o. to T2D rat model for 10 weeks. Morris water maze test, in vivo neuronal tracing, immunohistochemistry, and western blot analysis were performed to evaluate the protective effects of berberine in T2D-induced diabetic encephalopathy rats. Primary cultured neurons were used to further explore the underlying mechanisms in vitro. Results:Berberine dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Berberine significantly attenuated memory impairment, axonopathy, and tau hyperphosphorylation, and also restored PI3K/Akt/GSK3β signaling pathway in T2D rats. In vitro, berberine induced an increase in the phosphorylation of PI3K/Akt as well as GSK3β in high glucose-treated primary neurons. Furthermore, berberine-induced PI3K/Akt activation also resulted in the dephosphorylation of tau protein, which could improve axonal transport impairment in high glucose-treated primary neurons. Pretreated neurons with LY294002, an inhibitor of PI3K, partially blocked berberine-inhibited tau phosphorylation and berberine-activated PI3K/Akt signaling pathway. Conclusions:Berberine exerts the protective effect against cognitive deficits by improving tau hyperphosphorylation and the axonal damage through restoring PI3K/Akt/GSK3β signaling pathway.

Keywords: Axonopathy, berberine, diabetic encephalopathy, insulin, tau phosphorylation

DOI: 10.3233/JAD-180497

Journal: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1385-1400, 2018