1. Academic Validation
  2. Inhibition of mTORC1 improves STZ-induced AD-like impairments in mice

Inhibition of mTORC1 improves STZ-induced AD-like impairments in mice

  • Brain Res Bull. 2020 Sep;162:166-179. doi: 10.1016/j.brainresbull.2020.06.002.
Yun Cao 1 Bingjin Liu 2 Weiqi Xu 1 Lin Wang 1 Fangxiao Shi 1 Na Li 1 Ying Lei 1 Jianzhi Wang 1 Qing Tian 3 Xinwen Zhou 4
Affiliations

Affiliations

  • 1 Key Laboratory of Neurological Diseases of Education Ministry, Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
  • 2 School of Medicine and Pharmaceutical Engineering, Taizhou Vocational and Technical College, Taizhou 318000, PR China.
  • 3 Key Laboratory of Neurological Diseases of Education Ministry, Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China. Electronic address: tianq@mail.hust.edu.cn.
  • 4 Key Laboratory of Neurological Diseases of Education Ministry, Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China. Electronic address: zhouxinwen@hust.edu.cn.
Abstract

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share some pathological features, including tau hyperphosphorylation and deficits in Insulin signaling, but the underlying mechanism and effective drugs for treating AD are unknown. The AD-like brain impairments are almost same in both of mouse type 2 DM models induced by the multiple low-dose intraperitoneal (i.p.) streptozotocin (STZ) injection and twice intracerebroventricular (i.c.v.) STZ injection. We found that memory disorders, impairment of Insulin signaling, and AD-like tauopathies were exhibited in two different STZ-induced mouse models and that the level of Advanced Glycation End Products (AGEs) was increased in two STZ mouse models. Inhibition of mTORC1 with rapamycin reversed the deficits of Insulin signaling associated kinases activity, decreased levels of AGEs and AD-like tau phosphorylation, and also improved memory deficit in both STZ mice. Rapamycin attenuated HG-induced tau hyperphosphorylation via the Akt/AMPK/GSK-3β pathways and p70S6K in SH-SY5Y cells. Taken together, these data demonstrated that rapamycin improved STZ-induced AD-like tauopathies and memory deficit in mice via improving p70S6K and Akt/AMPK/GSK-3β signaling and decreasing AGEs. Therefore, regulating Insulin signaling via mTORC1 is a new strategy for preventing T2DM-associated AD, and mTORC1 is a potential drug target.

Keywords

Insulin signal; Memory disorder; Rapamycin; Tau hyperphosphorylation; mTORC1.

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