PMID- 20178983
OWN - NLM
STAT- MEDLINE
DCOM- 20100520
LR  - 20240419
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 17
DP  - 2010 Apr 23
TI  - Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, 
      and Tau: effects on cognitive impairments.
PG  - 13107-20
LID - 10.1074/jbc.M110.100420 [doi]
AB  - Accumulation of amyloid-beta (Abeta) and Tau is an invariant feature of Alzheimer 
      disease (AD). The upstream role of Abeta accumulation in the disease pathogenesis 
      is widely accepted, and there is strong evidence showing that Abeta accumulation 
      causes cognitive impairments. However, the molecular mechanisms linking Abeta to 
      cognitive decline remain to be elucidated. Here we show that the buildup of Abeta 
      increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing 
      mTOR signaling reduces Abeta levels, thereby highlighting an interrelation 
      between mTOR signaling and Abeta. The mTOR pathway plays a central role in 
      controlling protein homeostasis and hence, neuronal functions; indeed mTOR 
      signaling regulates different forms of learning and memory. Using an animal model 
      of AD, we show that pharmacologically restoring mTOR signaling with rapamycin 
      rescues cognitive deficits and ameliorates Abeta and Tau pathology by increasing 
      autophagy. Indeed, we further show that autophagy induction is necessary for the 
      rapamycin-mediated reduction in Abeta levels. The results presented here provide 
      a molecular basis for the Abeta-induced cognitive deficits and, moreover, show 
      that rapamycin, an FDA approved drug, improves learning and memory and reduces 
      Abeta and Tau pathology.
FAU - Caccamo, Antonella
AU  - Caccamo A
AD  - Department of Physiology, University of Texas Health Science Center, San Antonio, 
      Texas 78245, USA.
FAU - Majumder, Smita
AU  - Majumder S
FAU - Richardson, Arlan
AU  - Richardson A
FAU - Strong, Randy
AU  - Strong R
FAU - Oddo, Salvatore
AU  - Oddo S
LA  - eng
GR  - P30 AG013319/AG/NIA NIH HHS/United States
GR  - AG29729-4/AG/NIA NIH HHS/United States
GR  - K99 AG029729/AG/NIA NIH HHS/United States
GR  - 1P30-AG-13319/AG/NIA NIH HHS/United States
GR  - R00 AG029729/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20100223
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (tau Proteins)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Alzheimer Disease/drug therapy/genetics/*metabolism
MH  - Amyloid beta-Peptides/genetics/*metabolism
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Disease Models, Animal
MH  - Intracellular Signaling Peptides and Proteins/antagonists & 
      inhibitors/genetics/*metabolism
MH  - *Memory
MH  - Mice
MH  - Mice, Transgenic
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - *Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - tau Proteins/genetics/metabolism
PMC - PMC2857107
EDAT- 2010/02/25 06:00
MHDA- 2010/05/21 06:00
PMCR- 2011/04/23
CRDT- 2010/02/25 06:00
PHST- 2010/02/25 06:00 [entrez]
PHST- 2010/02/25 06:00 [pubmed]
PHST- 2010/05/21 06:00 [medline]
PHST- 2011/04/23 00:00 [pmc-release]
AID - S0021-9258(20)55089-8 [pii]
AID - M110.100420 [pii]
AID - 10.1074/jbc.M110.100420 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Apr 23;285(17):13107-20. doi: 10.1074/jbc.M110.100420. Epub 
      2010 Feb 23.