PMID- 23425014
OWN - NLM
STAT- MEDLINE
DCOM- 20130814
LR  - 20220330
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 12
IP  - 3
DP  - 2013 Jun
TI  - mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's 
      disease and other tauopathies.
PG  - 370-80
LID - 10.1111/acel.12057 [doi]
AB  - Accumulation of tau is a critical event in several neurodegenerative disorders, 
      collectively known as tauopathies, which include Alzheimer's disease and 
      frontotemporal dementia. Pathological tau is hyperphosphorylated and aggregates 
      to form neurofibrillary tangles. The molecular mechanisms leading to tau 
      accumulation remain unclear and more needs to be done to elucidate them. Age is a 
      major risk factor for all tauopathies, suggesting that molecular changes 
      contributing to the aging process may facilitate tau accumulation and represent 
      common mechanisms across different tauopathies. Here, we use multiple animal 
      models and complementary genetic and pharmacological approaches to show that the 
      mammalian target of rapamycin (mTOR) regulates tau phosphorylation and 
      degradation. Specifically, we show that genetically increasing mTOR activity 
      elevates endogenous mouse tau levels and phosphorylation. Complementary to it, we 
      further demonstrate that pharmacologically reducing mTOR signaling with rapamycin 
      ameliorates tau pathology and the associated behavioral deficits in a mouse model 
      overexpressing mutant human tau. Mechanistically, we provide compelling evidence 
      that the association between mTOR and tau is linked to GSK3beta and autophagy 
      function. In summary, we show that increasing mTOR signaling facilitates tau 
      pathology, while reducing mTOR signaling ameliorates tau pathology. Given the 
      overwhelming evidence that reducing mTOR signaling increases lifespan and 
      healthspan, the data presented here have profound clinical implications for aging 
      and tauopathies and provide the molecular basis for how aging may contribute to 
      tau pathology. Additionally, these results provide preclinical data indicating 
      that reducing mTOR signaling may be a valid therapeutic approach for tauopathies.
CI  - (c) 2013 John Wiley & Sons Ltd and the Anatomical Society.
FAU - Caccamo, Antonella
AU  - Caccamo A
AD  - Department of Physiology and The Barshop Institute for Longevity and Aging 
      Studies, University of Texas Health Science Center at San Antonio, 7703 Floyd 
      Curl Drive, San Antonio, TX 78229, USA.
FAU - Magri, Andrea
AU  - Magri A
FAU - Medina, David X
AU  - Medina DX
FAU - Wisely, Elena V
AU  - Wisely EV
FAU - Lopez-Aranda, Manuel F
AU  - Lopez-Aranda MF
FAU - Silva, Alcino J
AU  - Silva AJ
FAU - Oddo, Salvatore
AU  - Oddo S
LA  - eng
GR  - F30 AG043248/AG/NIA NIH HHS/United States
GR  - R01 AG037637/AG/NIA NIH HHS/United States
GR  - R01 MH084315/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130324
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (MAPT protein, human)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (tau Proteins)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Alzheimer Disease/metabolism
MH  - Amyloid beta-Peptides/metabolism
MH  - Animals
MH  - Autophagy
MH  - Disease Models, Animal
MH  - Frontotemporal Dementia/metabolism
MH  - Glycogen Synthase Kinase 3/metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - Humans
MH  - Immunosuppressive Agents/pharmacology
MH  - Mice
MH  - Mice, Transgenic
MH  - Microtubules/metabolism
MH  - Neurofibrillary Tangles/metabolism
MH  - Phosphorylation
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Tauopathies/genetics/*metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/*genetics
MH  - Up-Regulation
MH  - tau Proteins/*metabolism
PMC - PMC3655115
MID - NIHMS447420
EDAT- 2013/02/22 06:00
MHDA- 2013/08/15 06:00
PMCR- 2014/06/01
CRDT- 2013/02/22 06:00
PHST- 2013/02/05 00:00 [accepted]
PHST- 2013/02/22 06:00 [entrez]
PHST- 2013/02/22 06:00 [pubmed]
PHST- 2013/08/15 06:00 [medline]
PHST- 2014/06/01 00:00 [pmc-release]
AID - 10.1111/acel.12057 [doi]
PST - ppublish
SO  - Aging Cell. 2013 Jun;12(3):370-80. doi: 10.1111/acel.12057. Epub 2013 Mar 24.