The immunosuppressant rapamycin exacerbates neurotoxicity of Aβ peptide

Abstract

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. β‐Amyloid (Aβ) 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 Aβ 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 Aβ‐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 Aβ cell death is mediated via an mTOR‐independent pathway. These results demonstrate that mTOR plays an important role as a cellular survival pathway in Aβ toxicity and could represent a possible target for modulating Aβ toxicity. © 2006 Wiley‐Liss, Inc.