PMID- 21368103
OWN - NLM
STAT- MEDLINE
DCOM- 20110818
LR  - 20220225
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Print)
IS  - 0892-6638 (Linking)
VI  - 25
IP  - 6
DP  - 2011 Jun
TI  - A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via 
      Atg5-dependent autophagy pathway.
PG  - 1934-42
LID - 10.1096/fj.10-175158 [doi]
AB  - The hallmarks of Alzheimer's disease are the aggregates of amyloid-beta (Alphabeta) peptide 
      and tau protein. Autophagy is one major cellular pathway leading to the removal 
      of aggregated proteins. We examined the possibility of inducing autophagy to 
      reduce Abeta peptide and the amyloid precursor protein (APP)-derived fragment 
      APP-CTF levels in cell lines and primary neuronal cultures. We found that 
      induction of autophagy either by small-molecule enhancers of rapamycin (SMER)28, 
      a small-molecule enhancer of autophagy, or following starvation greatly decreased 
      the levels of Abeta peptide (apparent EC(50) of  approximately 10 muM) and APP-CTF (apparent EC(50) 
      of  approximately 20 muM) in a gamma-secretase-independent manner. Pharmacological inhibition of 
      autophagy led to a significant accumulation of Abeta peptide and APP-CTF and 
      diminished the effect of SMER28. Three essential components of the autophagic 
      pathway, autophagy-related protein (Atg)5, Beclin1, and Ulk1, were shown to be 
      involved in the degradation of Abeta and APP-CTF, and Atg5 was necessary for the 
      effect of SMER28. In addition, the autophagic marker light chain 3-II 
      cocompartmentalized with APP-CTF. These results support the involvement of 
      autophagy in the clearance of Abeta and APP-CTF. We therefore propose that small 
      molecule enhancers of autophagy, such as SMER28, may have therapeutic potential 
      for the treatment of Alzheimer's disease and other proteinopathies.
FAU - Tian, Yuan
AU  - Tian Y
AD  - Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, 1230 
      York Ave., New York, NY 10065, USA.
FAU - Bustos, Victor
AU  - Bustos V
FAU - Flajolet, Marc
AU  - Flajolet M
FAU - Greengard, Paul
AU  - Greengard P
LA  - eng
GR  - P01 AG009464/AG/NIA NIH HHS/United States
GR  - AG-09464/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110302
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (6-bromo-4-allylamino-quinazoline)
RN  - 0 (Allyl Compounds)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Atg5 protein, mouse)
RN  - 0 (Autophagy-Related Protein 5)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Quinazolines)
RN  - 0 (amyloid precursor protein carboxyl-terminal fragment gamma)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
SB  - IM
MH  - Allyl Compounds/metabolism
MH  - Amyloid Precursor Protein Secretases/metabolism
MH  - Amyloid beta-Protein Precursor/genetics/*metabolism
MH  - Animals
MH  - Autophagy/*physiology
MH  - Autophagy-Related Protein 5
MH  - Cells, Cultured
MH  - Fibroblasts/*metabolism
MH  - Gene Expression Regulation/physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Microtubule-Associated Proteins/genetics/*metabolism
MH  - Neuroblastoma/genetics/*metabolism
MH  - Neurons/metabolism/physiology
MH  - Peptide Fragments/genetics/*metabolism
MH  - Quinazolines/metabolism
MH  - Rats
PMC - PMC3101026
EDAT- 2011/03/04 06:00
MHDA- 2011/08/19 06:00
PMCR- 2012/06/01
CRDT- 2011/03/04 06:00
PHST- 2011/03/04 06:00 [entrez]
PHST- 2011/03/04 06:00 [pubmed]
PHST- 2011/08/19 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - fj.10-175158 [pii]
AID - 10-175158 [pii]
AID - 10.1096/fj.10-175158 [doi]
PST - ppublish
SO  - FASEB J. 2011 Jun;25(6):1934-42. doi: 10.1096/fj.10-175158. Epub 2011 Mar 2.