PMID- 24917666
OWN - NLM
STAT- MEDLINE
DCOM- 20150211
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 289
IP  - 30
DP  - 2014 Jul 25
TI  - Rapamycin and interleukin-1beta impair brain-derived neurotrophic factor-dependent 
      neuron survival by modulating autophagy.
PG  - 20615-29
AB  - The mammalian target of rapamycin (mTOR) pathway has multiple important 
      physiological functions, including regulation of protein synthesis, cell growth, 
      autophagy, and synaptic plasticity. Activation of mTOR is necessary for the many 
      beneficial effects of brain-derived neurotrophic factor (BDNF), including 
      dendritic translation and memory formation in the hippocampus. At present, 
      however, the role of mTOR in BDNF's support of survival is not clear. We report 
      that mTOR activation is necessary for BDNF-dependent survival of primary rat 
      hippocampal neurons, as either mTOR inhibition by rapamycin or genetic 
      manipulation of the downstream molecule p70S6K specifically blocked BDNF rescue. 
      Surprisingly, however, BDNF did not promote neuron survival by up-regulating 
      mTOR-dependent protein synthesis or through mTOR-dependent suppression of 
      caspase-3 activation. Instead, activated mTOR was responsible for BDNF's 
      suppression of autophagic flux. shRNA against the autophagic machinery Atg7 or 
      Atg5 prolonged the survival of neurons co-treated with BDNF and rapamycin, 
      suggesting that suppression of mTOR in BDNF-treated cells resulted in excessive 
      autophagy. Finally, acting as a physiological analog of rapamycin, IL-1beta impaired 
      BDNF signaling by way of inhibiting mTOR activation as follows: the cytokine 
      induced caspase-independent neuronal death and accelerated autophagic flux in 
      BDNF-treated cells. These findings reveal a novel mechanism of BDNF 
      neuroprotection; BDNF not only prevents apoptosis through inhibiting caspase 
      activation but also promotes neuron survival through modulation of autophagy. 
      This protection mechanism is vulnerable under chronic inflammation, which 
      deregulates autophagy through impairing mTOR signaling. These results may be 
      relevant to age-related changes observed in neurodegenerative diseases.
FAU - Smith, Erica D
AU  - Smith ED
FAU - Prieto, G Aleph
AU  - Prieto GA
FAU - Tong, Liqi
AU  - Tong L
FAU - Sears-Kraxberger, Ilse
AU  - Sears-Kraxberger I
FAU - Rice, Jeffrey D
AU  - Rice JD
FAU - Steward, Oswald
AU  - Steward O
FAU - Cotman, Carl W
AU  - Cotman CW
LA  - eng
GR  - T32 MH014599/MH/NIMH NIH HHS/United States
GR  - P01 AG000538/AG/NIA NIH HHS/United States
GR  - MH14599-29/MH/NIMH NIH HHS/United States
GR  - P01-AG000538/AG/NIA NIH HHS/United States
GR  - R01 NS073857/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Atg5 protein, rat)
RN  - 0 (Atg7 protein, rat)
RN  - 0 (Autophagy-Related Protein 5)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (IL1B protein, rat)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Proteins)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.22.- (Casp3 protein, rat)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 6.2.1.45 (Autophagy-Related Protein 7)
RN  - EC 6.2.1.45 (Ubiquitin-Activating Enzymes)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Autophagy/*drug effects
MH  - Autophagy-Related Protein 5
MH  - Autophagy-Related Protein 7
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Caspase 3/metabolism
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Immunosuppressive Agents/*pharmacology
MH  - Interleukin-1beta/*metabolism
MH  - Male
MH  - Neurodegenerative Diseases/metabolism/pathology
MH  - Neurons/*metabolism/pathology
MH  - Proteins/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Ubiquitin-Activating Enzymes/metabolism
PMC - PMC4110274
EDAT- 2014/06/12 06:00
MHDA- 2015/02/12 06:00
PMCR- 2015/07/25
CRDT- 2014/06/12 06:00
PHST- 2014/06/12 06:00 [entrez]
PHST- 2014/06/12 06:00 [pubmed]
PHST- 2015/02/12 06:00 [medline]
PHST- 2015/07/25 00:00 [pmc-release]
AID - S0021-9258(20)47584-2 [pii]
AID - M114.568659 [pii]
AID - 10.1074/jbc.M114.568659 [doi]
PST - ppublish
SO  - J Biol Chem. 2014 Jul 25;289(30):20615-29. doi: 10.1074/jbc.M114.568659.