PMID- 29729422
OWN - NLM
STAT- MEDLINE
DCOM- 20181016
LR  - 20231014
IS  - 1558-1497 (Electronic)
IS  - 0197-4580 (Print)
IS  - 0197-4580 (Linking)
VI  - 68
DP  - 2018 Aug
TI  - Genetically reducing mTOR signaling rescues central insulin dysregulation in a 
      mouse model of Alzheimer's disease.
PG  - 1
LID - S0197-4580(18)30121-0 [pii]
LID - 10.1016/j.neurobiolaging.2018.03.032 [doi]
AB  - Alzheimer's disease (AD) is the most common neurodegenerative disease. The causes 
      of sporadic AD, which represents more than 95% of AD cases, are unknown. Several 
      AD risk factors have been identified and among these, type 2 diabetes increases 
      the risk of developing AD by 2-fold. However, the mechanisms by which diabetes 
      contributes to AD pathogenesis remain elusive. The mammalian target of rapamycin 
      (mTOR) is a protein kinase that plays a crucial role in the insulin signaling 
      pathway and has been linked to AD. We used a crossbreeding strategy to remove 1 
      copy of the mTOR gene from the forebrain of Tg2576 mice, a mouse model of AD. We 
      used 20-month-old mice to assess changes in central insulin signaling and found 
      that Tg2576 mice had impaired insulin signaling. These impairments were mTOR 
      dependent as we found an improvement in central insulin signaling in mice with 
      lower brain mTOR activity. Furthermore, removing 1 copy of mTOR from Tg2576 mice 
      improved cognition and reduced levels of Abeta, tau, and cytokines. Our findings 
      indicate that mTOR signaling is a key mediator of central insulin dysfunction in 
      Tg2576. These data further highlight a possible role for mTOR signaling in AD 
      pathogenesis and add to the body of evidence indicating that reducing mTOR 
      activity could be a valid therapeutic approach for AD.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Caccamo, Antonella
AU  - Caccamo A
AD  - The Arizona State University-Banner, Neurodegenerative Disease Research Center at 
      the Biodesign Institute, Arizona State University, Tempe, AZ, USA.
FAU - Belfiore, Ramona
AU  - Belfiore R
AD  - The Arizona State University-Banner, Neurodegenerative Disease Research Center at 
      the Biodesign Institute, Arizona State University, Tempe, AZ, USA; Department of 
      Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
FAU - Oddo, Salvatore
AU  - Oddo S
AD  - The Arizona State University-Banner, Neurodegenerative Disease Research Center at 
      the Biodesign Institute, Arizona State University, Tempe, AZ, USA; School of Life 
      Sciences, Arizona State University, Tempe, AZ, USA.
LA  - eng
GR  - R01 AG037637/AG/NIA NIH HHS/United States
GR  - RF1 AG037637/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Retracted Publication
DEP - 20180405
PL  - United States
TA  - Neurobiol Aging
JT  - Neurobiology of aging
JID - 8100437
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Cytokines)
RN  - 0 (Insulin)
RN  - 0 (tau Proteins)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
RIN - Neurobiol Aging. 2021 Aug;104:139. PMID: 34162481
MH  - Alzheimer Disease/*etiology/*genetics/metabolism/therapy
MH  - Amyloid beta-Peptides/metabolism
MH  - Animals
MH  - Brain/metabolism
MH  - Cognition
MH  - Cytokines/metabolism
MH  - Diabetes Mellitus, Type 2/complications/genetics
MH  - Disease Models, Animal
MH  - *Gene Dosage
MH  - Insulin/*metabolism
MH  - Mice, Transgenic
MH  - Molecular Targeted Therapy
MH  - Signal Transduction/*genetics/*physiology
MH  - TOR Serine-Threonine Kinases/*genetics/*metabolism/physiology
MH  - tau Proteins/metabolism
PMC - PMC6777740
MID - NIHMS957861
OTO - NOTNLM
OT  - AD
OT  - Amyloid beta
OT  - Abeta
OT  - Diabetes
OT  - Glucose
OT  - Tangles
OT  - Tau
COIS- Declaration of interest Conflict of interest: None
EDAT- 2018/05/08 06:00
MHDA- 2018/10/17 06:00
PMCR- 2019/10/04
CRDT- 2018/05/06 06:00
PHST- 2017/09/20 00:00 [received]
PHST- 2018/03/28 00:00 [revised]
PHST- 2018/03/29 00:00 [accepted]
PHST- 2018/05/08 06:00 [pubmed]
PHST- 2018/10/17 06:00 [medline]
PHST- 2018/05/06 06:00 [entrez]
PHST- 2019/10/04 00:00 [pmc-release]
AID - S0197-4580(18)30121-0 [pii]
AID - 10.1016/j.neurobiolaging.2018.03.032 [doi]
PST - ppublish
SO  - Neurobiol Aging. 2018 Aug;68:1. doi: 10.1016/j.neurobiolaging.2018.03.032. Epub 
      2018 Apr 5.