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-

One of the pathological hallmarks of Alzheimer's disease (AD) is deposition of extracellular amyloid-␤ (A␤) peptide, which is generated from the cleavage of amyloid precursor protein (APP). Accumulation of A␤ is thought to associate with the progressive neuronal death observed in AD. However, the precise signaling mechanisms underlying the action of A␤ in AD pathophysiology are not completely understood. Here, we report the involvement of the transcription factor signal transducer and activator of transcription 3 (STAT3) in mediating A␤-induced neuronal death. We find that tyrosine phosphorylation of STAT3 is elevated in the cortex and hippocampus of APP/PS1 transgenic mice. Treatment of cultured rat neurons with A␤ or intrahippocampal injection of mice with A␤ both induces tyrosine phosphorylation of STAT3 in neurons. Importantly, reduction of either the expression or activation of STAT3 markedly attenuates A␤-induced neuronal apoptosis, suggesting that STAT3 activation contributes to neuronal death after A␤ exposure. We further identify Tyk2 as the tyrosine kinase that acts upstream of STAT3, as A␤-induced activation of STAT3 and caspase-3-dependent neuronal death can be inhibited in tyk2 Ϫ/Ϫ neurons. Finally, increased tyrosine phosphorylation of STAT3 is also observed in postmortem brains of AD patients. Our observations collectively reveal a novel role of STAT3 in A␤-induced neuronal death and suggest the potential involvement of Tyk2/STAT3 signaling in AD pathophysiology.

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BackgroundAutophagy is a major pathway of protein and organelle degradation in the lysosome. Autophagy exists at basal constitutive level and can be induced as a defense mechanism under stress conditions. Molecular relationships between autophagy and inflammation at the periphery were recently evidenced, highlighting a role of autophagy in the regulation of inflammation. Impairment of autophagy (with accumulation of autophagic vacuoles) and substantial inflammation are found in neurodegenerative diseases such as Alzheimer’s Disease (AD). However, the links between autophagy and inflammation in AD remain to be determined.MethodsHere, we examined the inflammatory reaction and autophagy in murine tri-cultures of neurons, astrocytes, and microglia. Tri-cultures were exposed to various inflammatory stresses (lipopolysaccharide (LPS), amyloid peptide (Aβ42) with or without cytokines) for 48 hours. Furthermore, the relationships between inflammation and autophagy were also analyzed in astrocyte- and microglia-enriched cultures. Data for multiple variable comparisons were analyzed by a one-way ANOVA followed by a Newman-keuls’ test.ResultsAβ42 induced a low inflammation without accumulation of acidic vesicles contrary to moderate or severe inflammation induced by LPS or the cytokine cocktail (IL-1β, TNF-α, and IL-6) or IL-1β alone which led to co-localization of p62 and LC3, two markers of autophagy, with acidic vesicles stained with Lyso-ID Red dye. Moreover, the study reveals a major role of IL-1β in the induction of autophagy in tri-cultures in the presence or absence of Aβ42. However, the vulnerability of the autophagic process in purified microglia to IL-1β was prevented by Aβ42.ConclusionThese findings show a close relationship between inflammation and autophagy, in particular a major role of IL-1β in the induction of the microglial autophagy which could be the case in AD. New therapeutic strategies could target inflammasome and autophagy in microglia to maintain its role in the amyloid immunosurveillance.

Loera-Valencia R, Cedazo-Minguez A, ). Current and emerging avenues for Alzheimer's disease drug targets (Review). J Intern Med 2019; 286: 398-437.Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Ab) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Ab and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy. ReviewInsoluble Ab fibrils are taken into consideration as the main responsible for spine pathology. On the other hand, in both transgenic mouse models of AD and human AD brain, synapse defects and memory loss correlate weakly with the presence of Ab Current and novel Alzheimer´s disease therapy targets / R. Loera-Valencia et al.