mTOR/p70S6k signalling alteration by Aβ exposure as well as in APP‐PS1 transgenic models and in patients with Alzheimer's disease

Abstract

In Alzheimer's disease, neuropathological hallmarks include the accumulation of b-amyloid peptides (Ab) in senile plaques, phosphorylated tau in neurofibrillary tangles and neuronal death. Ab 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. Ab 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. Keywords: Alzheimer, Ab, human lymphocytes, mTOR signalling, transgenic models, translation. In eukaryotes, protein translation includes three consecutive phases: initiation, elongation and termination. The initiation phase corresponds to processes associated with the connection between mRNA and ribosomes. The elongation phase includes the links between amino acids at the ribosomal level, and is followed by the termination phase. These three phases are highly regulated by proteins, called translation factors, that can interact directly with mRNAs. In the initiation phase, two major factors are involved: eukaryotic initiation factor 2 (eIF2) and eukaryotic initiation factor 4E (eIF4E).The availability of eIF4E is linked to the binding of specific proteins called 4E-BPs. When these proteins are not phosphorylated, they have a great affinity for eIF4E, which is unable to bind to mRNAs, leading to a reduction of translation. These proteins are mainly phosphorylated by a kinase called mTOR (mammalian target of rapamycin) or FKBP12-

Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau

“…It is clear, however, that the role of mTOR in AD is very complex; although it is established that in human AD brains mTOR signaling is increased, especially in neurons predicted to develop Tau pathology, diverging results have been published on the effects of A␤ on mTOR signaling in cell lines. For example, A␤ application to differentiated N2A neuroblastoma cells following 10% serum deprivation significantly decreases the levels of phosphorylated p70S6K (64), whereas differentiated human SH-SY5Y cells exposed to A␤42 show an increase in phosphorylation levels of p70S6K (65). Our data showing an increase in p70S6K phosphorylation in 7PA2 cells are consistent with the latter but appear to be conflicting with the effects of A␤ on N2A cells.…”

“…The role of autophagy in AD is not well understood and contradicting reports have been published. For example, it has been reported that autophagic vacuoles may be a source of A␤ production and that autophagic vacuoles accumulate in AD brains and in APP/PS1 transgenic mice, thus suggesting that an increase in autophagy may lead to a further accumulation of A␤ (64,66,67). In contrast, other reports show that autophagy protects neurons from A␤ toxicity (59,60,68,69).…”

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

“…We found that hippocampal p70S6K level suppressed following Aβ injection that was prevented by GA pretreatment, concurrent with improvement in PA memory. In this manner, both in vitro and in vivo administration of Aβ by Lafay-Chebassier et al (2005) resulted in significant decrease in p70S6K signaling. Although in another independent study of AD patients there was an aberrant activation of p70S6K, it was attributed to neurofibrillary pathology and tau phosphorylation, not Aβ .…”

Biphasic Activation of the mTOR Pathway in the Gustatory Cortex Is Correlated with and Necessary for Taste Learning

“…( Lafay-Chebassier et al, 2005;Paccalin et al, 2006a,b). Based on these data, we studied the role of the mTOR pathway as a specific translation regulator in the cortex after acquiring novel sensory information.…”