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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.

In Alzheimer’s disease (AD), the control of translation is dysregulated, precisely, two opposite pathways: double‐stranded RNA‐dependent protein kinase (PKR) is up‐regulated and mammalian target of rapamycin (mTOR) is down‐regulated. These biochemical alterations were found at the periphery in lymphocytes of AD patients and were significantly correlated with cognitive and memory test scores. However, the molecular crosslink between these two opposite signalling pathways remains unknown. The tumour suppressor p53 and Redd1 (regulated in development and DNA damage response) could be two downstream targets of active PKR to explain the breakdown of translation in AD patients. In this study, the protein and gene levels of p53 and Redd1 were assayed in lymphocytes of AD patients and in age‐matched controls by Western blotting and RT‐PCR. Furthermore, correlations were analysed with both the level of active PKR and the Mini Mental State Examination score (MMSE). The results show that the gene and protein levels of p53 and Redd1 were significantly increased about 1.5‐fold for both gene and Redd1 protein and 2.3‐fold for active p53 in AD lymphocytes compared to age‐matched controls. Furthermore, statistical correlations between proteins and genes suggest that active PKR could phosphorylate p53 which could induce the transcription of Redd1 gene. No correlations were found between MMSE scores and levels of p53 or Redd1, contrary to active PKR levels. PKR represents a cognitive decline biomarker able to dysregulate translation via two consecutive targets p53 and Redd1 in AD lymphocytes.

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