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-

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Iatrogenic amnesia is one of the main aetiologies of transient amnesia.• Benzodiazepines and anticholinergic drugs are considered to be the drugs most often responsible for iatrogenic amnesia.• The impact of drugs in memory disorders is particularly pronounced in elderly people, especially due to polymedication.WHAT THIS STUDY ADDS• An association between memory disorders and some drugs, such as benzodiazepines, antidepressants and older anticonvulsants, was found as expected.• A strong association was found with unexpected drugs, such as benzodiazepine‐like hypnotics (zopiclone and zolpidem), serotonin reuptake inhibitor antidepressants and newer anticonvulsants.• Non‐neurotropic drugs, such as isotretinoin and ciclosporin, were also associated with memory disorders.AIMS To investigate putative associations of reports of memory disorders and suspected drugs.METHODS We used the case/noncase method in the French PharmacoVigilance Database (FPVD). Cases were reports of memory loss in the FPVD between January 2000 and December 2009. Noncases were all other reports during the same period. To assess the association between memory impairment and drug intake, we calculated an odds ratio with its 95% confidence interval.RESULTS Among the 188 284 adverse drug reactions recorded, we identified 519 cases of memory loss. The sex ratio was 0.6 and the median age was 54 years (range 4–93). The maximal number of cases occurred between 40–49 and 50–59 years. Evolution was favourable in 63% of the cases. We found significant odds ratios for benzodiazepines (alprazolam, bromazepam, prazepam, clonazepam etc.), benzodiazepine‐like hypnotics (zolpidem and zopiclone), antidepressants (fluoxetine, paroxetine and venlafaxine), analgesics (morphine, nefopam and tramadol), anticonvulsants (topiramate, pregabalin, levetiracetam etc.), antipsychotics (aripiprazole and lithium) and other drugs, such as trihexyphenidyl, ciclosporin and isotretinoin.CONCLUSIONS Our study confirmed an association between memory disorders and some drugs, such as benzodiazepines and anticonvulsants. However, other drugs, such as benzodiazepine‐like hypnotics, newer anticonvulsants, serotonin reuptake inhibitor antidepressants, isotretinoin and ciclosporin were significantly associated with memory disorders, although this was not described or poorly described in the literature.Taking account of the limits of this study in the FPVD (under‐reporting, notoriety bias etc.), the case/noncase method allows assessment and detection of associations between exposure to drugs and a specific adverse drug reaction, such as memory disorders, and could thus generate signals and orientate us to further prospective studies to confirm such associations.

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 A␤25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the A␤25-35 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 A␤25-35 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

Inhibition of double-stranded RNA-dependent protein kinase (PKR) represents an interesting strategy for neuroprotection. However, inhibiting this kinase which triggers the apoptotic process could favour in counterpart cell proliferation and tumorigenesis. Here, we use an in vivo model of 7-day-old rat displaying a high activation of brain PKR to investigate the effects of a new PKR inhibitor identified as an oxindole/imidazole derivative (C16). We show for the first time that acute systemic injection of C16 specifically inhibits the apoptotic PKR/eIF2a signaling pathway without stimulating the proliferative mTOR/p70S6K signaling mechanism.