PMID- 32599128
OWN - NLM
STAT- MEDLINE
DCOM- 20210929
LR  - 20210929
IS  - 1873-2747 (Electronic)
IS  - 0361-9230 (Linking)
VI  - 162
DP  - 2020 Sep
TI  - Inhibition of mTORC1 improves STZ-induced AD-like impairments in mice.
PG  - 166-179
LID - S0361-9230(20)30510-4 [pii]
LID - 10.1016/j.brainresbull.2020.06.002 [doi]
AB  - 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-3beta 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-3beta 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.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Cao, Yun
AU  - Cao Y
AD  - Key Laboratory of Neurological Diseases of Education Ministry, Department of 
      Pathophysiology, Tongji Medical College, Huazhong University of Science and 
      Technology, Wuhan 430030, PR China.
FAU - Liu, Bingjin
AU  - Liu B
AD  - School of Medicine and Pharmaceutical Engineering, Taizhou Vocational and 
      Technical College, Taizhou 318000, PR China.
FAU - Xu, Weiqi
AU  - Xu W
AD  - Key Laboratory of Neurological Diseases of Education Ministry, Department of 
      Pathophysiology, Tongji Medical College, Huazhong University of Science and 
      Technology, Wuhan 430030, PR China.
FAU - Wang, Lin
AU  - Wang L
AD  - Key Laboratory of Neurological Diseases of Education Ministry, Department of 
      Pathophysiology, Tongji Medical College, Huazhong University of Science and 
      Technology, Wuhan 430030, PR China.
FAU - Shi, Fangxiao
AU  - Shi F
AD  - Key Laboratory of Neurological Diseases of Education Ministry, Department of 
      Pathophysiology, Tongji Medical College, Huazhong University of Science and 
      Technology, Wuhan 430030, PR China.
FAU - Li, Na
AU  - Li N
AD  - Key Laboratory of Neurological Diseases of Education Ministry, Department of 
      Pathophysiology, Tongji Medical College, Huazhong University of Science and 
      Technology, Wuhan 430030, PR China.
FAU - Lei, Ying
AU  - Lei Y
AD  - Key Laboratory of Neurological Diseases of Education Ministry, Department of 
      Pathophysiology, Tongji Medical College, Huazhong University of Science and 
      Technology, Wuhan 430030, PR China.
FAU - Wang, Jianzhi
AU  - Wang J
AD  - Key Laboratory of Neurological Diseases of Education Ministry, Department of 
      Pathophysiology, Tongji Medical College, Huazhong University of Science and 
      Technology, Wuhan 430030, PR China.
FAU - Tian, Qing
AU  - Tian Q
AD  - 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.
FAU - Zhou, Xinwen
AU  - Zhou X
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200627
PL  - United States
TA  - Brain Res Bull
JT  - Brain research bulletin
JID - 7605818
RN  - 0 (Immunosuppressive Agents)
RN  - 5W494URQ81 (Streptozocin)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Alzheimer Disease/drug therapy/*metabolism
MH  - Animals
MH  - Cell Line, Tumor
MH  - Diabetes Mellitus, Experimental/chemically induced/drug therapy/*metabolism
MH  - Humans
MH  - Immunosuppressive Agents/pharmacology/therapeutic use
MH  - Male
MH  - Maze Learning/drug effects/physiology
MH  - Mechanistic Target of Rapamycin Complex 1/*antagonists & inhibitors/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Sirolimus/pharmacology/*therapeutic use
MH  - Streptozocin/*toxicity
OTO - NOTNLM
OT  - Insulin signal
OT  - Memory disorder
OT  - Rapamycin
OT  - Tau hyperphosphorylation
OT  - mTORC1
COIS- Declaration of Competing Interest The authors declare that they have no conflict 
      of interest.
EDAT- 2020/07/01 06:00
MHDA- 2021/09/30 06:00
CRDT- 2020/06/30 06:00
PHST- 2020/04/21 00:00 [received]
PHST- 2020/05/29 00:00 [revised]
PHST- 2020/06/03 00:00 [accepted]
PHST- 2020/07/01 06:00 [pubmed]
PHST- 2021/09/30 06:00 [medline]
PHST- 2020/06/30 06:00 [entrez]
AID - S0361-9230(20)30510-4 [pii]
AID - 10.1016/j.brainresbull.2020.06.002 [doi]
PST - ppublish
SO  - Brain Res Bull. 2020 Sep;162:166-179. doi: 10.1016/j.brainresbull.2020.06.002. 
      Epub 2020 Jun 27.