Solas, M. (Maite)
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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.
- Trimethylamine N-oxide (TMAO) drives insulin resistance and cognitive deficiencies in a senescence accelerated mouse model(Elsevier, 2022) Pineda-Lucena, A. (Antonio); Puerta, E. (Elena); Ludwig, I.A. (Iziar Amaia); Ramirez, M.J. (María Javier); Milagro-Yoldi, F.I. (Fermín Ignacio); Solas, M. (Maite); Janeiro-Arenas, M.H. (Manuel Humberto); Lanz, M. (María)It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases.
- 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.
- Insulin levels are decreased in the cerebrospinal fluid of women with prodomal Alzheimer's disease(Ios Press, 2010) Ramirez, M.J. (María Javier); Kivipelto, M. (Miia); Solas, M. (Maite); Mugueta, C. (Carmen); Gil-Bea, F.J. (Francisco J.); Cedazo-Minguez, A. (Ángel); Solomon, A. (Alina)Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-β 1-42 (Aβ1-42) levels and cognitive score. Furthermore, total-tau/(Aβ1-42*insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aβ1-42 ratio for early AD diagnosis in women.
- DHA selectively protects SAMP-8-Associated cognitive deficits through inhibition of JNK(Springer, 2019) Vela, S. (S.); Moreno-Aliaga, M. J. (María Jesús); Ramirez, M.J. (María Javier); Solas, M. (Maite)A potential role of marine n-3 polyunsaturated fatty acids (ω-3 PUFAs) has been suggested in memory, learning, and cognitive processes. Therefore, ω-3 PUFAs might be a promising treatment option, albeit controversial, for Alzheimer's disease (AD). Among the different mechanisms that have been proposed as responsible for the beneficial effects of ω-3 PUFAs, inhibition of JNK stands as a particularly interesting candidate. In the present work, it has been studied whether the administration of two different PUFAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and a DHA-derived specialized pro-resolving lipid mediator (MaR1) is able to reverse cognitive deficits in the senescence-accelerated mouse prone 8 (SAMP8) mouse model of sporadic AD. The novel object recognition test (NORT) test showed that recognition memory was significantly impaired in SAMP8 mice, as shown by a significantly decreased discrimination index that was reversed by MaR1 and DHA. In the retention phase of the Morris water maze (MWM) task, SAMP8 mice showed memory deficit that only DHA treatment was able to reverse. pJNK levels were significantly increased in the hippocampus of SAMP8 mice compared to SAMR1 mice, and only DHA treatment was able to significantly reverse these increased pJNK levels. Similar results were found when measuring c-Jun, the main JNK substrate. Consequently to the increases in tau phosphorylation after increased pJNK, it was checked that tau phosphorylation (PHF-1) was increased in SAMP mice, and this effect was reversed after DHA treatment. Altogether, DHA could represent a new approach for the treatment of AD through JNK inhibition.
- 5-HT7 receptors in Alzheimer’s disease(Elsevier, 2021) Ocariz-Díez, U. (Urtzi); Ramirez, M.J. (María Javier); Janssens, J. (Jana); Solas, M. (Maite); Vermeiren, Y. (Yannick); Van-Dam, D. (Debby); De-Deyn, P.P. (Peter Paul)Even though the involvement of serotonin (5-hydroxytryptamine; 5-HT) and its receptors in Alzheimer's disease (AD) is widely accepted, data on the expression and the role of 5-HT7 receptors in AD is relatively limited. Therefore, the objective of the present work was to study the expression of serotonergic 5-HT7 receptors in postmortem samples of AD brains and correlate it with neurotransmitter levels, cognition and behavior. The study population consisted of clinically well-characterized and neuropathologically confirmed AD patients (n = 42) and age-matched control subjects (n = 18). Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and high-performance liquid chromatography were performed on Brodmann area (BA) 7, BA10, BA22, BA24, hippocampus, amygdala, thalamus and cerebellum to measure mRNA levels of 5-HT7 receptors (HTR7), as well as the concentrations of various monoamine neurotransmitters and their metabolites. Decreased levels of HTR7 mRNA were observed in BA10. A significant association was observed between HTR7 levels in BA10 and BEHAVE-AD cluster B (hallucinations) (rs(28) = 0.444, P < 0.05). In addition, a negative correlation was observed between HTR7 levels in BA10 and both MHPG concentrations in this brain region (rs(45) = -0.311; P < 0.05), and DOPAC levels in the amygdala (rs(42) = -0.311; P < 0.05). Quite surprisingly, no association was found between HTR7 levels and cognitive status. Altogether, this study supports the notion of the involvement of 5-HT7 receptors in psychotic symptoms in AD, suggesting the interest of testing antagonist acting at this receptor to specifically treat psychotic symptoms in this illness.
- Increased levels of brain adrenomedullin in the neuropathology of Alzheimer's Disease(2018) Martinez, J.A. (José Alfredo); Larrayoz, I.M. (Ignacio M.); Ramirez, M.J. (María Javier); Francis, P.T. (Paul T.); Howlett, D.R. (David R.); Solas, M. (Maite); Gil-Bea, F.J. (Francisco J.); Martisova, E. (Eva); Ferrero-Hidalgo, H. (Hilda)Alzheimer's disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD.
- Reduced adrenomedullin parallels microtubule dismantlement in frontotemporal lobar degeneration(2018) Martinez, J.A. (José Alfredo); Larrayoz, I.M. (Ignacio M.); Ramirez, M.J. (María Javier); Solas, M. (Maite); Gil-Bea, F.J. (Francisco J.); Ferrero-Hidalgo, H. (Hilda)Tau is a microtubule-associated protein highly expressed in neurons with a chief role in microtubule dynamics and axonal maintenance. Adrenomedullin gene (ADM) codifies for various peptides that exert broad range of actions in the body. Previous works in our groups have shown that increased ADM products are positively correlated to microtubule disruption and tau pathology in Alzheimer's disease brains. In the present study, we explore the involvement of ADM in the neuropathology of frontotemporal lobar degeneration that presents with primary tauopathy (FTLD-tau). Proteins from frontal cortices of FTLD-tau patients and age- and sex-matched non-demented controls were analyzed with antibodies against different microtubule components, including adrenomedullin, and synaptic markers. Tau pathology in frontal cortex from FTLD patients was confirmed. Levels of total βIII-tubulin as well as acetylated and detyrosinated tubulins, two markers of stabilized and aged microtubules, were significantly reduced and directly correlated with PSD95 and proBDNF in FTLD-tau patients when compared to non-demented controls. In contrast, no change in actin cytoskeleton was found. Interestingly, changes in microtubule elements, indicators of disturbed axonal preservation, were accompanied by decreased levels of free adrenomedullin, although no association was found. Altogether, reduced levels of adrenomedullin might not be directly linked to the microtubule pathology of FTLD-tau, but based on previous works, it is suggested that downregulation of ADM might be an adaptive attempt of neurons to mitigate microtubule disruption.
- 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.
- Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target(2018) Martinez, J.A. (José Alfredo); Ramirez, M.J. (María Javier); Milagro-Yoldi, F.I. (Fermín Ignacio); Solas, M. (Maite); Janeiro-Arenas, M.H. (Manuel Humberto)Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.