Research Center Biomedica en Red para Enfermedades Neurodegenerativas

Madrid, Spain

Research Center Biomedica en Red para Enfermedades Neurodegenerativas

Madrid, Spain
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Texido L.,University of Barcelona | Texido L.,Research Center Biomedica en Red Para Enfermedades Neurodegenerativas | Hernandez S.,University of Lleida | Martin-Satue M.,University of Barcelona | And 9 more authors.
Neurochemistry International | Year: 2011

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the selective loss of both upper and lower motoneurons (MNs). The familial form of the illness is associated with mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD-1) enzyme, but it accounts for fewer than 10% of cases; the rest, more than 90%, correspond to the sporadic form of ALS. Although many proposals have been suggested over the years, the mechanisms underlying the characteristic selective killing of MN in ALS remain unknown. In this study we tested the effect of sera from sporadic ALS patients on NMDA receptors (NMDAR). We hypothesize that an endogenous seric factor is implicated in neuronal death in ALS, mediated by the modulation of NMDAR. Sera from ALS patients and from healthy subjects were pretreated to inactivate complement pathways and dialyzed to remove glutamate and glycine. IgGs from ALS patients and healthy subjects were obtained by affinity chromatography and dialyzed against phosphate-buffered saline. Human NMDAR were expressed in Xenopus laevis oocytes, and ionic currents were recorded using the two-electrode voltage clamp technique. Sera from sporadic ALS patients induced transient oscillatory currents in oocytes expressing NMDAR with a significantly higher total electrical charge than that induced by sera from healthy subjects. Sera from patients with other neuromuscular diseases did not exert this effect. The currents were inhibited by MK-801, a noncompetitive blocker of NMDAR. The PLC inhibitor, U-73122, and the IP3 receptor antagonist, 2-APB, also inhibited the sera-induced currents. The oscillatory signal recorded was due to internal calcium mobilization. Isolated IgGs from ALS patients significantly affected the activity of oocytes injected with NMDAR, causing a 2-fold increase over the response recorded for IgGs from healthy subjects. Our data support the notion that ALS sera contain soluble factors that mobilize intracellular calcium, not opening directly the ionic conductance, but through the non-canonical activation of NMDAR. © 2011 Elsevier B.V. All rights reserved.


Badiola N.,Hospital Of Sant Pau | Badiola N.,Research Center Biomedica en Red para enfermedades Neurodegenerativas | de Oliveira R.M.,Institute Medicina Molecular | Herrera F.,Institute Medicina Molecular | And 13 more authors.
PLoS ONE | Year: 2011

Background: The simultaneous accumulation of different misfolded proteins in the central nervous system is a common feature in many neurodegenerative diseases. In most cases, co-occurrence of abnormal deposited proteins is observed in different brain regions and cell populations, but, in some instances, the proteins can be found in the same cellular aggregates. Co-occurrence of tau and α-synuclein (α-syn) aggregates has been described in neurodegenerative disorders with primary deposition of α-syn, such as Parkinson's disease and dementia with Lewy bodies. Although it is known that tau and α-syn have pathological synergistic effects on their mutual fibrillization, the underlying biological effects remain unclear. Methodology/Principal Findings: We used different cell models of synucleinopathy to investigate the effects of tau on α-syn aggregation. Using confocal microscopy and FRET-based techniques we observed that tau colocalized and interacted with α-syn aggregates. We also found that tau overexpression changed the pattern of α-syn aggregation, reducing the size and increasing the number of aggregates. This shift was accompanied by an increase in the levels of insoluble α-syn. Furthermore, co-transfection of tau increased secreted α-syn and cytotoxicity. Conclusions/Significance: Our data suggest that tau enhances α-syn aggregation and toxicity and disrupts α-syn inclusion formation. This pathological synergistic effect between tau and α-syn may amplify the deleterious process and spread the damage in neurodegenerative diseases that show co-occurrence of both pathologies. © 2011 Badiola et al.


Rubio S.E.,Barcelona Institute for Research in Biomedicine | Rubio S.E.,University of Barcelona | Rubio S.E.,Research Center Biomedica en Red para Enfermedades Neurodegenerativas | Vega-Flores G.,Pablo De Olavide University | And 18 more authors.
FASEB Journal | Year: 2012

Patients with Alzheimer's disease (AD) display altered functioning of cortical networks, including altered patterns of synchronous activity and a serious deficit in cholinergic septohippocampal (SH) innervation. However, the mechanisms underlying these alterations and the implication of the GABAergic SH component in AD are largely unknown. In addition, the GABAergic septohippocampal pathway (SHP) is believed to regulate synchronous hippocampal activity by controlling the activity of interneurons. Here we show, using well-characterized pathway tracing experiments, that innervation of the GABAergic SHP decreases during normal aging. Furthermore, in an AD mouse model (hAPPSw,Ind; J20 mice), the GABAergic SHP shows a dramatic and early onset of this decrease in 8-mo-old mice. This decline is not caused by neuronal loss, but by the reduced number and complexity of GABAergic SH axon terminals. Finally, we demonstrate that hippocampal θ and γ rhythm power spectra are markedly diminished in 8-mo-old behaving mice expressing mutated hAPP. In addition to the well-known loss of cholinergic input to the hippocampus in AD, these data suggest that the altered patterns of synchronous activity seen in patients with AD could be caused by the loss of GABAergic SH axons, which modulate hippocampal network activities. © FASEB.


Perez-Diaz H.,Hospital Clinico Of Barcelona | Perez-Diaz H.,Research Center Biomedica en Red para Enfermedades Neurodegenerativas | Iranzo A.,Hospital Clinico Of Barcelona | Iranzo A.,Research Center Biomedica en Red para Enfermedades Neurodegenerativas | And 2 more authors.
Neurologia | Year: 2010

Objective: To present five patients with zolpidem-induced sleep-related behavioural disorders. Methods: Evaluation using a questionnaire designed to study sleep behaviours and past medical history in all patients. Results: The patients performed complex actions while sleep-walking (telephoning, house-cleaning, feeding the dog or waxing their legs). Inappropriate feeding behaviour with excessive food intake during the night were reported by all patients. All had weight gain, which in one patient led to extreme obesity. Two patients suffered injuries (knife cuts and burns) related to attempting to prepare food. One patient took a laxative. Conclusion: Withdrawal of zolpidem resolved the behaviours in all cases, highlighting the importance of an adequate diagnosis of this side effect. © 2009 Sociedad Española de Neurología.


Vega-Flores G.,Pablo De Olavide University | Rubio S.E.,Barcelona Institute for Research in Biomedicine | Rubio S.E.,University of Barcelona | Rubio S.E.,Research Center Biomedica en Red Para Enfermedades Neurodegenerativas | And 12 more authors.
Cerebral Cortex | Year: 2014

We studied the role of γ-aminobutyric acid (GABA)ergic septohippocampal projections in medial septum (MS) self-stimulation of behaving mice. Self-stimulation was evoked in wild-type (WT) mice using instrumental conditioning procedures and in J20 mutant mice, a type of mouse with a significant deficit in GABAergic septohippocampal projections. J20 mice showed a significant modification in hippocampal activities, including a different response for input/ output curves and the paired-pulse test, a larger long-term potentiation (LTP), and a delayed acquisition and lower performance in the MS self-stimulation task. LTP evoked at the CA3-CA1 synapse further decreased self-stimulation performance in J20, but not in WT, mice. MS self-stimulation evoked a decrease in the amplitude of field excitatory postsynaptic potentials (fEPSPs) at the CA3-CA1 synapse in WT, but not in J20, mice. This self-stimulation-dependent decrease in the amplitude of fEPSPs was also observed in the presence of another positive reinforcer (food collected during an operant task) and was canceled by the local administration of an antibody-inhibiting glutamate decarboxylase 65 (GAD65). LTP evoked in the GAD65Ab-treated group was also larger than in controls. The hippocampus has a different susceptibility to septal GABAergic inputs depending on ongoing cognitive processes, and the GABAergic septohippocampal pathway is involved in consummatory processes related to operant rewards. © The Author 2013.

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