The relation between p70S6k expression in lymphocytes and the decline of cognitive test scores in patients with Alzheimer disease

Université de Poitiers, Poitiers, Poitou-Charentes, France
Archives of Internal Medicine (Impact Factor: 17.33). 12/2005; 165(20):2428-9. DOI: 10.1001/archinte.165.20.2428
Source: PubMed
9 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: The control of translation, involving the kinases mTOR (mammalian target of rapamycin) and PKR (double-stranded RNA-dependent protein kinase), modulates cell survival and death and is altered in the brains of patients with Alzheimer's disease (AD). In AD increased susceptibility of lymphocytes to apoptosis has been reported. We investigated the level of the kinases mTOR and PKR and the eukaryotic initiation factor 2alpha (eIF2alpha) in lymphocytes of patients with AD in comparison with controls. In AD patients we also looked for a correlation between activated proteins and cognitive and memory tests. We report significant alterations of the levels of these kinases and eIF2alpha in lymphocytes of AD patients that were also significantly correlated with cognitive and memory test scores. These results suggest that the levels of mTOR, PKR and eIF2alpha in lymphocytes could follow the cognitive decline in AD.
    No preview · Article · Feb 2006 · Dementia and Geriatric Cognitive Disorders
  • [Show abstract] [Hide abstract]
    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. 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.
    No preview · Article · Nov 2006 · Journal of Neuroscience Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is clinically marked at the onset, by memory disturbances affecting explicit memory. Emotional explicit memory is enhanced in normal subjects and remained less affected at the beginning of AD. The kinase p70S6k participates in the control of protein translation and seems also implicated in the process of synaptic plasticity and the formation of memory at the molecular level. In a previous study, we have shown that peripheral p70S6k level is correlated with the decline of cognitive and memory functions in patients with AD. The goal of the present study was to analyse emotional and neutral explicit memory in AD patients and to evaluate the levels of active p70S6k in lymphocytes by western blots. The results reveal that the difference between emotional and neutral memories are correlated with the levels of peripheral p70S6k in patients with AD, as well as with the global cognitive scores assessed by the Mini Mental Status Examination. The decline of emotional memory in AD patients is reflected by the decrease of p70S6k levels.
    No preview · Article · Jan 2007 · Neuroscience Letters
Show more