Exosomes are small vesicles (60-100 nm) secreted by various cell types upon the fusion of endosomal compartments with the plasma membrane. Exosomes from antigen-presenting cells (APC), such as B lymphocytes and dendritic cells (DC), bear MHC class II molecules. In addition, the injection of DC-derived exosomes was reported to elicit potent T cell responses in vivo. Here, we analyzed the activation of specific T cells by MHC class II-bearing exosomes in vitro. The rat mast cell line, RBL-2H3, was engineered to express human class II molecules uniformly loaded with an antigenic peptide [HLA-DR1-hemagglutinin (HA)]. These cells secreted exosomes bearing DR1 class II molecules upon stimulation by a calcium ionophore or IgE receptor cross-linking. Exosomes bearing DR1-HA(306-318) complexes activated HA/DR1-specific T cells only weakly, whereas the cross-linking of such exosomes to latex beads increased stimulation of specific T cells. By contrast, the incubation of free exosomes with DC resulted in the highly efficient stimulation of specific T cells. Thus, exosomes bearing MHC class II complexes must be taken up by professional APC for efficient T cell activation.
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-
Background: 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. Methods: We investigated the level of the kinases mTOR and PKR and the eukaryotic initiation factor 2α (eIF2α) 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. Results: We report significant alterations of the levels of these kinases and eIF2α in lymphocytes of AD patients that were also significantly correlated with cognitive and memory test scores. Conclusion: These results suggest that the levels of mTOR, PKR and eIF2α in lymphocytes could follow the cognitive decline in AD.
Alzheimer's disease (AD), the most common form of dementia in the older people, is a multifactoral pathology, characterized by cognitive deficits, increase in cerebral deposition of the -amyloid (A) peptide, neurofibrillary tangles, and neurodegeneration. Studies currently support a central role of neuroinflammation, through production of proinflammatory cytokines including excess tumor necrosis factor ␣ (TNF-␣) in the pathogenesis of AD, especially in A-induced cognitive deficits. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and neuroprotective effects. This study investigates the effect of imipramine on alterations of long-term and short-term memories, TNF-␣ expression, and amyloid precursor protein (APP) processing induced by intracerebroventricular injection of A25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the A25-35 injection. Memory function was evaluated in the water-maze (days 10 -14) and Y-maze (day 9) tests. TNF-␣ levels and APP processing were examined in the frontal cortex and the hippocampus (day 14). Imipramine significantly prevented memory deficits caused by A25-35 in the water-maze and Y-maze tests, and inhibited the TNF-␣ increase in the frontal cortex. Moreover, imipramine decreased the elevated levels of A both in frontal cortex and hippocampus with different modulations of APP and C-terminal fragments of APP. So, imipramine prevents memory impairment through its intrinsic property to inhibit TNF-␣ and A accumulation and may represent a potential candidate for AD treatment.Alzheimer's disease (AD), the most common form of dementia in older people is associated with cognitive deficits. Indeed, brains of individuals who have AD manifest massive neuronal and synaptic loss in certain areas that result in memory impairment and disorientation associated mainly with late stages of the disease. However, in the early stages, the etiology of these cognitive dysfunctions is unclear. AD is a multifactoral pathology, characterized not only by an increase in cerebral deposition of the -amyloid (A) peptide, the major constituent of senile plaques that can potentially cause cognitive impairments, but also by neuroinflammation, oxidative damage, and neurodegeneration in critical brain regions (hippocampus, frontal cortex) also involved in memory and cognition
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.
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