The immunosuppressant rapamycin exacerbates neurotoxicity of Abeta peptide.
Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system characterized by two major lesions: extracellular senile plaques and intraneuronal neurofibrillary tangles. beta-Amyloid (Abeta) is known to play a major role in the pathogenesis of AD. Protein synthesis and especially translation initiation are modulated by different factors, including the PKR/eIF2 and the mTOR/p70S6K pathways. mRNA translation is altered in the brain of AD patients. Very little is known about the translation control mediated by mTOR in AD, although mTOR is a central regulator of translation initiation and also ribosome biogenesis and cell growth and proliferation. In this study, by using Western blotting, we show that mTOR pathway is down-regulated by Abeta treatment in human neuroblastoma cells, and the underlying mechanism explaining a transient activation of p70S6K is linked to cross-talk between mTOR and ERK1/2 at this kinase level. This phenomenon is associated with caspase-3 activation, and inhibition of mTOR by the inhibitor rapamycin enhances Abeta-induced cell death. Moreover, in our cell model, insulin-like growth factor-1 is able to increase markedly the p70S6K phosphorylation controlled by mTOR and reduces the caspase-3 activity, but its protective effect on Abeta cell death is mediated via an mTOR-independent pathway. These results demonstrate that mTOR plays an important role as a cellular survival pathway in Abeta toxicity and could represent a possible target for modulating Abeta toxicity.
Lafay-Chebassier
Claire
C
Research Group on Brain Aging (EA 3808), University of Poitiers, Poitiers, France. claire.lafay@univ-poitiers.fr
Pérault-Pochat
Marie Christine
MC
Page
Guylène
G
Rioux Bilan
Agnès
A
Damjanac
Milena
M
Pain
Stéphanie
S
Houeto
Jean-Luc
JL
Gil
Roger
R
Hugon
Jacques
J
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005456:Fluorescent Dyes; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007211:Indoles; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D009447:Neuroblastoma / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity*; D011494:Protein Kinases / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D007211:Indoles; D009498:Neurotoxins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C007293:DAPI; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D020123:Sirolimus