PMID- 15953364
OWN - NLM
STAT- MEDLINE
DCOM- 20050808
LR  - 20220225
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 94
IP  - 1
DP  - 2005 Jul
TI  - mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 
      transgenic models and in patients with Alzheimer's disease.
PG  - 215-25
AB  - In Alzheimer's disease, neuropathological hallmarks include the accumulation of 
      beta-amyloid peptides (Abeta) in senile plaques, phosphorylated tau in 
      neurofibrillary tangles and neuronal death. Abeta is the major aetiological agent 
      according to the amyloid cascade hypothesis. Translational control includes 
      phosphorylation of the kinases mammalian target of rapamycin (mTOR) and p70S6k 
      which modulate cell growth, proliferation and autophagy. It is mainly part of an 
      anti-apoptotic cellular signalling. In this study, we analysed modifications of 
      mTOR/p70S6k signalling in cellular and transgenic models of Alzheimer's disease, 
      as well as in lymphocytes of patients and control individuals. Abeta 1-42 
      produced a rapid and persistent down-regulation of mTOR/p70S6k phosphorylation in 
      murine neuroblastoma cells associated with caspase 3 activation. Using western 
      blottings, we found that phosphorylated forms of mTOR and p70S6k are decreased in 
      the cortex but not in the cerebellum (devoid of plaques) of double APP/PS1 
      transgenic mice compared with control mice. These results were confirmed by 
      immunohistochemical methods. Finally, the expression of phosphorylated p70S6k was 
      significantly reduced in lymphocytes of Alzheimer's patients, and levels of 
      phosphorylated p70S6k were statistically correlated with Mini Mental Status 
      Examination (MMSE) scores. Taken together, these findings demonstrate that the 
      mainly anti-apoptotic mTOR/p70S6k signalling is altered in cellular and 
      transgenic models of Alzheimer's disease and in peripheral cells of patients, and 
      could contribute to the pathogenesis of the disease.
FAU - Lafay-Chebassier, Claire
AU  - Lafay-Chebassier C
AD  - Department of Pharmacology, Poitiers University Hospital, France.
FAU - Paccalin, Marc
AU  - Paccalin M
FAU - Page, Guylene
AU  - Page G
FAU - Barc-Pain, Stephanie
AU  - Barc-Pain S
FAU - Perault-Pochat, Marie Christine
AU  - Perault-Pochat MC
FAU - Gil, Roger
AU  - Gil R
FAU - Pradier, Laurent
AU  - Pradier L
FAU - Hugon, Jacques
AU  - Hugon J
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Membrane Proteins)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (Presenilin-1)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Alzheimer Disease/metabolism/pathology
MH  - Amyloid beta-Peptides/metabolism/*physiology
MH  - Amyloid beta-Protein Precursor/*genetics/physiology
MH  - Animals
MH  - Apoptosis/genetics/physiology
MH  - Brain/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Female
MH  - Humans
MH  - Male
MH  - Membrane Proteins/*genetics/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred CBA
MH  - Mice, Transgenic
MH  - Middle Aged
MH  - Presenilin-1
MH  - Protein Kinases/genetics/*physiology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/genetics/*physiology
MH  - Signal Transduction/*physiology
MH  - TOR Serine-Threonine Kinases
EDAT- 2005/06/15 09:00
MHDA- 2005/08/09 09:00
CRDT- 2005/06/15 09:00
PHST- 2005/06/15 09:00 [pubmed]
PHST- 2005/08/09 09:00 [medline]
PHST- 2005/06/15 09:00 [entrez]
AID - JNC3187 [pii]
AID - 10.1111/j.1471-4159.2005.03187.x [doi]
PST - ppublish
SO  - J Neurochem. 2005 Jul;94(1):215-25. doi: 10.1111/j.1471-4159.2005.03187.x.