Aisa, B. (Bárbara)

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    Altered NCAM expression associated with the cholinergic system in Alzheimer's disease
    (Ios Press, 2010) Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Chen, C.P. (Christopher P.); Francis, P.T. (Paul T.); Garcia-Alloza, M. (Mónica); Lai, M.K. (Mitchell K.); Solas, M. (Maite); Gil-Bea, F.J. (Francisco J.)
    Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer's disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson's product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n=19; r=0.526*; p=0.037) as well as in temporal cortex (n=19; r=0.601*; p=0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD.
  • Long term sex-dependent psychoneuroendocrine effects of maternal deprivation and juvenile unpredictable stress in rats
    (Blackwell Publishing, 2011) Llorente, R. (R.); Lachize, S. (S.); Aisa, B. (Bárbara); Meijer, O.C. (O. C.); Ramirez, M.J. (María Javier); Borcel, E. (E.); Miguel-Blanco, C. (C.); Viveros, M.P. (M.P.); Kloet, E.R. (E. R.) de
    We have analysed the long-term psychoneuroendocrine effects of maternal deprivation (MD) [24 h at postnatal day (PND) 9] and/or exposure to chronic unpredictable stress (CUS) during the periadolescent period (PND 28 to PND 43) in male and female Wistar rats. Animals were tested in the elevated plus maze (EPM, anxiety) at PND 44 and in two memory tests, spontaneous alternation and novel object recognition (NOT) in adulthood. The expression of hippocampal glucocorticoid (GR) and mineralocorticoid (MR) receptors, as well as of synaptophysin, neural cell adhesion molecule and brain-derived neurotrophic factor, was analysed by in situ hybridisation in selected hippocampal regions. Endocrine determinations of leptin, testosterone and oestradiol plasma levels were carried out by radioimmunoassay. Young CUS animals showed decreased anxiety behaviour in the EPM (increased percentage of time and entries in the open arms) irrespective of neonatal treatment. Memory impairments were induced by the two stressful treatments as was revealed by the NOT, with males being most clearly affected. Although each stressful procedure, when considered separately, induced different (always decrements) effects on the three synaptic molecules analysed and affected males and females differently, the combination of MD and CUS induced an unique disruptive effect on the three synaptic plasticity players. MD induced a long-term significant decrease in hippocampal GR only in males, whereas CUS tended to increase MR in males and decrease MR in females. Both neonatal MD and periadolescent CUS induced marked reductions in testosterone and oestradiol in males, whereas MD male animals also showed significantly decreased leptin levels. By contrast, in females, none of the hormones analysed was altered by any of the stressful procedures. Taking our data together in support of the 'two-hit' hypothesis, MD during neonatal life and/or exposure to CUS during the periadolescent period induced a permanent deficit in memory, which was accompanied by a decrement in markers for hippocampal plasticity. The long-term effects on body weight and hormone levels, particularly among males, might reflect sex-dependent lasting metabolic alterations as well as an impaired reproductive function.
  • Increase of locomotor activity underlying the behavioral disinhibition in tg2576 mice
    (American Psychological Association, 2007) Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Gil-Bea, F.J. (Francisco J.); Schliebs, R. (Reinhard)
    The transgenic Tg2576 mouse is a widely used animal model that develops some of the cognitive and neuropathological deteriorations observed in patients suffering Alzheimer's disease. The authors investigated 9-month-old Tg2576 mice with respect to behavioral and endocrinological (hypothalamic- pituitary-adrenal [HPA] axis activity) parameters. The locomotor activity test revealed that Tg2576 mice moved almost twice as much as controls. Tg2576 mice spent significantly more time visiting the open arms and performed more entries into these open arms than did controls. However, the amount of time that Tg2576 mice remained in each entry to the open arm was similar to that of controls, and the number of arm entries correlated positively to locomotor activity. In the forced swimming test, Tg2576 mice showed a significant decrease in immobility time, which correlated negatively to locomotor activity. Parameters of the HPA axis, such as plasma level of corticosterone, adrenal gland weight, and noradrenaline or adrenaline release, did not differ between controls and Tg2576 mice. These data suggest that the disinhibitory behavior of Tg2576 mice seems to be related to increased locomotor activity but not to any disturbance of the HPA axis.
  • HPA axis dysregulation associated to apolipoprotein E4 genotype in Alzheimer's disease
    (IOS Press, 2010) Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Kivipelto, M. (Miia); Solas, M. (Maite); Mugueta, C. (Carmen); Winblad, B. (Bengt); Gil-Bea, F.J. (Francisco J.); Cedazo-Minguez, A. (Ángel); Solomon, A. (Alina)
    The present work investigated the involvement of cortisol and its receptors, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), in Alzheimer's disease (AD). Cortisol was measured in cerebrospinal fluid (CSF) samples from controls, mild cognitive impairment (MCI), progressive MCI evolving to AD, and AD. CSF cortisol levels do not seem to have a prognostic value, as increases in cortisol levels were found only in AD patients. GR expression was decreased while MR expression was increased in the frontal cortex of AD. When considering degeneration (ratio to synaptophysin and the post-synaptic marker PSD95), GR expression was similar between controls and AD, suggesting that GR loss was due to synaptic degeneration in AD. Increases in cortisol levels and MR expression were associated to an apolipoprotein E4 genotype. Cognitive status was negatively associated to CSF cortisol. In apolipoprotein E4 carriers, MR but not GR expression, negatively correlated to Mini-Mental Status Examination score and positively correlated to frontal cortex amyloid-β levels. It is concluded that there is a dysregulation of the hypothalamus-pituitary-adrenal axis in AD that seems to be consequence rather than cause of AD.
  • Involvement of the Serotonergic System in Cognitive and Behavioral Symptoms of Alzheimer's Disease
    (Bentham Science Publishers, 2005) Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Garcia-Alloza, M. (Mónica); Gil-Bea, F.J. (Francisco J.); Marcos, B. (Beatriz)
    Alzheimer's disease (AD) is a chronic progressive disorder characterized by dementia, but often featuring behavioral and psychological syndromes (BPSD), such as depression, overactivity, psychosis or aggressive behavior. Traditional treatments for BPSD are neuroleptics and sedatives, which are not devoid of serious adverse effects. Neurochemically, the classical hallmark of AD is the disruption of basal forebrain cholinergic pathways and consequent cortical cholinergic denervation of the neocortex and hippocampus. However, it is conceivable that, according to the complexity and diversity of BPSD, more than one transmitter system may contribute to a particular behavioral syndrome. The serotonergic system has been implicated not only in cognitive processes, but also in depression, psychosis or aggression. In AD, extensive serotonergic denervation has been reported. In particular, there is growing interest in the pathological functions and implication in BPSD of 5-HT6 receptors, due to its high affinity for antipsychotic drugs and its distribution in the brain. In this study we will review the present knowledge of the involvement of the serotonergic system and its receptors in cognitive deficits and BPSD. From the currently available data, it is possible to conclude that pharmacological manipulation of serotonergic system may improve not only cognitive function but behavioral disturbances in dementia.
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    Novel Benzo[b]thiophene Derivatives as New Potential Antidepressants with Rapid Onset of Action
    (American Chemical Society, 2011) Aldana, I. (Ignacio); Levy, F.O. (Finn Olav); Guccione, S. (S.); Moltzau, L.R. (Lise Roman); Nicoletti, F. (Ferdinando); Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Pérez-Silanes, S. (Silvia); Galiano, S. (Silvia); Monge, A. (Antonio); Molinaro, G. (Gemma); Battaglia, G. (G.); Berrade, L. (Luis)
    We report benzo[b]thiophene derivatives synthesized according to a dual strategy. 8j, 9c, and 9e with affinity values toward 5-HT7R and 5-HTT were selected to probe using the forced swimming text (FST). The results showed significant antidepressant activity after chronic treatment. 9c was effective in reducing the immobility time in FST even after acute treatment. These findings identify these compounds as a new class of antidepressants with a rapid onset of action.
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    Interactions between age, stress and insulin on cognition: implications for Alzheimer's disease
    (Nature, 2010-07) Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Solas, M. (Maite); Mugueta, C. (Carmen); Rio, J. (Joaquín) del; Tordera, R.M. (Rosa María)
    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.
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    Stress-induced anhedonia is associated to increased Alzheimer's disease markers
    (Wiley-Blackwell, 2012) Gagno, S. (S.); Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Solas, M. (Maite); Martisova, E. (Eva); Tordera, R.M. (Rosa María); Dobarro, M. (M.); Briones, A. (A.)
    Background and purpose: stress is believed to be associated with the development of neuropsychiatric disorders, including Alzheimer's disease (AD). We have studied mechanism implicated in vulnerability to stress and the relationship with changes in AD-related markers. Key results: when using the chronic mild stress (CMS) paradigm to induce anhedonia, 40% percent of rats were resistant to the development of anhedonia (CMSR), whereas the remaining were responsive (CMSA). Only CMSA rats displayed significant increases in immobility time in the forced swimming test, cognitive deficits in the novel object recognition test and significant decreases in synaptophysin, pAkt and pERK1/2 expression in the hippocampus. Increased levels of Aβ40, β-secretase (BACE1) and Tau phosphorylation were also found only in CMSA rats. Interestingly, all these effects in CMSA rats were reverted by normalization of the HPA axis activity by pharmacological treatment with the antidepressant venlafaxine. Conclusions and implications: It is proposed that vulnerability to stress might be related to development of AD pathology and that venlafaxine might be considered as a new therapeutical approach for the treatment of AD.
  • Effects of chronic blockade of 5-HT(6) receptors on NMDA receptor subunits expression
    (Wiley Blackwell, 2009) Chuang, T.T. (Tsu T.); Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Gil-Bea, F.J. (Francisco J.); Marcos, B. (Beatriz)
  • Long-lasting behavioral effects and recognition memory deficit induced by chronic mild stress in mice: effect of antidepressant treatment
    (Springer Verlag, 2008) Elizalde, N. (N.); Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Lasheras, B. (Berta); Gil-Bea, F.J. (Francisco J.); Rio, J. (Joaquín) del; Tordera, R.M. (Rosa María)
    RATIONALE: Many studies support the validity of the chronic mild stress (CMS) model of depression in rodents. However, most of them focus on analysis of reactivity to rewards during the CMS and/or depressive-like behavior shortly after stress. In this study, we investigate acute and long-term effects of CMS and antidepressant treatment on depressive, anxiety-like behavior and learning. MATERIALS AND METHODS: Mice (C57BL/6) were exposed to CMS for 6 weeks and anhedonia was evaluated by weekly monitoring of sucrose intake. Paroxetine (10 mg kg(-1)day(-1) i.p.) or saline were administered the last 3 weeks of CMS and continued for 2 weeks thereafter. Behavioral tests were performed over the last week of CMS (acute effects) and 1 month later (long-term effects). RESULTS: Mice exposed to CMS displayed both acute and long-term decreased sucrose intake, increased immobility in the forced swimming test (FST) and impaired memory in the novel object recognition test. It is interesting to note that a correlation was found between the cognitive deficits and the helpless behavior in the FST induced by CMS. During the CMS procedure, paroxetine treatment reverted partially recognition memory impairment but failed to prevent the increased immobility in the FST. Moreover, it decreased on its own sucrose intake. Importantly, the long-term effects of CMS were partially prevented by chronic paroxetine. CONCLUSIONS: CMS leads to a long-term altered behavioral profile that could be partially reverted by chronic antidepressant treatment. This study brings novel features regarding the long-term effects of CMS and on the predictive validity of this depression animal model.