Interactions between age, stress and insulin on cognition: implications for Alzheimer's disease

There is much interest in understanding the mechanisms responsible for interactions among stress, aging, memory and Alzheimer's disease. Glucocorticoid secretion associated with early life stress may contribute to the variability of the aging process and to the development of neuro- and psychopathologies. Maternal separation (MS), a model of early life stress in which rats experience 3 h of daily separation from the dam during the first 3 weeks of life, was used to study the interactions between stress and aging. Young (3 months) MS rats showed an altered hypothalamic-pituitary-adrenal (HPA) axis reactivity, depressive-like behavior in the Porsolt swimming test and cognitive impairments in the Morris water maze and new object recognition test that persisted in aged (18 months) rats. Levels of insulin receptor, phosphorylated insulin receptor and markers of downstream signaling pathways (pAkt, pGSK3 beta, pTau, and pERK1 levels) were significantly decreased in aged rats. There was a significant decrease in pERK2 and in the plasticity marker ARC in MS aged rats compared with single MS or aged rats. It is interesting to note that there was a significant increase in the C99 : C83 ratio, A beta levels, and BACE1 levels the hippocampus of MS aged rats, suggesting that in aged rats subjected to early life stress, there was an increase in the amyloidogenic processing of amyloid precursor protein (APP). These results are integrated in a tentative mechanism through which aging interplay with stress to influence cognition as the basis of Alzheimer disease (AD). The present results may provide the proof-of-concept for the use of glucocorticoid-/insulin-related drugs in the treatment of AD

Regulation of markers of synaptic function in mouse models of depression: chronic mild stress and decreased expression of VGLUT1

Depression has been linked to failure in synaptic plasticity originating from environmental and/or genetic risk factors. The chronic mild stress (CMS) model regulates the expression of synaptic markers of neurotransmitter function and associated depressive-like behaviour. Moreover, mice heterozygous for the synaptic vesicle protein (SVP) vesicular glutamate transporter 1 (VGLUT1), have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, mechanisms of failure in synaptic plasticity, common to stress and impaired glutamate function. First, we show that CMS induced a transient decrease of different plasticity markers (VGLUT1, synapsin 1, sinaptophysin, rab3A and activity regulated cytoskeletal protein Arc) but a long-lasting decrease of the brain derived neurotrophic factor (BDNF) as well as depressive-like behaviour. The immediate early gene (IEG) Arc was also downregulated in VGLUT1+/- heterozygous mice. In contrast, an opposite regulation of synapsin 1 was observed. Finally, both models showed a marked increase of cortical Arc response to novelty. Increased Arc response to novelty could be suggested as a molecular mechanism underlying failure to adapt to environmental changes, common to chronic stress and altered glutamate function. Further studies should investigate whether these changes are associated to depressive-like behaviour both in animal models and in depressed patients

Role of HDAC5 and SIRT2 in depression and clinical efficacy of antidepressants

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Role of HDAC5 and SIRT2 in depression and clinical efficacy of antidepressants

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HDAC5 y SIRT2, dos dianas farmacológicas implicadas en el fenotipo depresivo y en la acción antidepresiva

Depression is a chronic disabling disorder mainly characterized by anhedonia and depressed mood, and still unresolved in terms of aetiology and response to treatment. Growing evidence suggests that epigenetic mechanisms play a key role in neuronal plasticity, and, therefore, mediate stable functional changes in the brain in response to environmental stimuli. Specifically, stress-mediated epigenetic changes in limbic regions that can persist for a lifetime, could contribute to the pathogenesis of depression. Likewise, antidepressant therapy might be achieved in part via epigenetic mechanisms. Moreover, epigenetic modifications could establish the basis for the interindividual variability in vulnerability to adversity and/or response to treatment. It was observed that chronic stress induced epigenetic changes in histone remodelling affecting expression of genes involved in neural plasticity. Specifically, two histone deacetylases, Hdac5 and Sirt2, which were oppositely regulated by stress and antidepressant drug in the prefrontal cortex of mice, were identified. These enzymes could contribute to stable stress-induced neuronal adaptations. In addition, repeated reboxetine treatment increased the phosphorylated form of HDAC5 (P-HDAC5), indicating that noradrenaline mediates cytoplasmic export of this enzyme. Moreover, SIRT2 was downregulated by all monoaminergic antidepressants (fluoxetine, reboxetine and imipramine) suggesting that these effects could contribute to the well-known beneficial effects of antidepressants on brain plasticity. Finally, correlating with what it happens with antidepressant treatment, repeated treatment with specific Hdacs inhibitors for three weeks increased synaptic plasticity in the prefrontal cortex. Moreover, using the compound 33i, reported as a selective SIRT2 inhibitor in vitro, it was shown that SIRT2 inhibition modulates glutamate and serotonin systems in the mouse prefrontal cortex and induced an antidepressant-like action. It is highlighted the therapeutic potential of SIRT2 as a new pharmacological target for the treatment of major depression and the need to further investigate the role of SIRT2 inhibitors as antidepressant agents. In summary, this study supports the hypothesis that associates major depression and antidepressant therapy with epigenetic changes that may explain the large inter-individual variability of response to adversity or treatment

HDAC5 y SIRT2, dos dianas farmacológicas implicadas en el fenotipo depresivo y en la acción antidepresiva

Depression is a chronic disabling disorder mainly characterized by anhedonia and depressed mood, and still unresolved in terms of aetiology and response to treatment. Growing evidence suggests that epigenetic mechanisms play a key role in neuronal plasticity, and, therefore, mediate stable functional changes in the brain in response to environmental stimuli. Specifically, stress-mediated epigenetic changes in limbic regions that can persist for a lifetime, could contribute to the pathogenesis of depression. Likewise, antidepressant therapy might be achieved in part via epigenetic mechanisms. Moreover, epigenetic modifications could establish the basis for the interindividual variability in vulnerability to adversity and/or response to treatment. It was observed that chronic stress induced epigenetic changes in histone remodelling affecting expression of genes involved in neural plasticity. Specifically, two histone deacetylases, Hdac5 and Sirt2, which were oppositely regulated by stress and antidepressant drug in the prefrontal cortex of mice, were identified. These enzymes could contribute to stable stress-induced neuronal adaptations. In addition, repeated reboxetine treatment increased the phosphorylated form of HDAC5 (P-HDAC5), indicating that noradrenaline mediates cytoplasmic export of this enzyme. Moreover, SIRT2 was downregulated by all monoaminergic antidepressants (fluoxetine, reboxetine and imipramine) suggesting that these effects could contribute to the well-known beneficial effects of antidepressants on brain plasticity. Finally, correlating with what it happens with antidepressant treatment, repeated treatment with specific Hdacs inhibitors for three weeks increased synaptic plasticity in the prefrontal cortex. Moreover, using the compound 33i, reported as a selective SIRT2 inhibitor in vitro, it was shown that SIRT2 inhibition modulates glutamate and serotonin systems in the mouse prefrontal cortex and induced an antidepressant-like action. It is highlighted the therapeutic potential of SIRT2 as a new pharmacological target for the treatment of major depression and the need to further investigate the role of SIRT2 inhibitors as antidepressant agents. In summary, this study supports the hypothesis that associates major depression and antidepressant therapy with epigenetic changes that may explain the large inter-individual variability of response to adversity or treatment

Serotonergic Therapies for Cognitive Symptoms in Alzheimer's Disease: Rationale and Current Status

10.1007/s40265-014-0217-5DRUGS747729-736NEW ZEALAN

Nucleocytoplasmic export of HDAC5 and SIRT2 downregulation: two epigenetic mechanisms by which antidepressants enhance synaptic plasticity markers

Rationale: Antidepressant action has been linked to increased synaptic plasticity in which epigenetic mechanisms such as histone posttranslational acetylation could be involved. Interestingly, the histone deacetylases HDAC5 and SIRT2 are oppositely regulated by stress and antidepressants in mice prefrontal cortex (PFC). Besides, the neuroblastoma SH-SY5Y line is an in vitro neuronal model reliable to study drug effects with clear advantages over animals. Objectives: We aimed to characterize in vitro the role of HDAC5 and SIRT2 in antidepressant regulation of neuroplasticity. Methods: SH-SY5Y cultures were incubated with imipramine, fluoxetine, and reboxetine (10 μM, 2 and 24 h) as well as the selective HDAC5 (MC3822, 5 μM, 24 h) or SIRT2 (33i, 5 μM, 24 h) inhibitors. The regulation of the brain-derived neurotrophic factor (BDNF), the vesicular glutamate transporter 1 (VGLUT1), the acetylated histones 3 (AcH3) and 4 (AcH4), HDAC5, and SIRT2 was studied. Comparatively, the long-term effects of these antidepressants (21 days, i.p.) in the mice (C57BL6, 8 weeks) PFC were studied. Results: Antidepressants increased both in vitro and in vivo expression of BDNF, VGLUT1, AcH3, and AcH4. Moreover, imipramine and reboxetine increased the phosphorylated form of HDAC5 (P-HDAC5), mediating its cytoplasmic export. Further, SIRT2 was downregulated by all antidepressants. Finally, specific inhibition of HDAC5 and SIRT2 increased neuroplasticity markers. Conclusions: This study supports the validity of the SH-SY5Y model for studying epigenetic changes linked to synaptic plasticity induced by antidepressants as well as the effect of selective HDAC inhibitors. Particularly, nucleocytoplasmic export of HDAC5 and SIRT2 downregulation mediated by antidepressants could enhance synaptic plasticity markers leading to antidepressant action