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Lopez-Gonzalez I.,Bellvitge Hospital Universitari Of Bellvitge | Schluter A.,Institute Dinvestigacio Biomedica Of Bellvitge | Schluter A.,Center for Biomedical Research on Rare Diseases | Aso E.,Bellvitge Hospital Universitari Of Bellvitge | And 16 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2015

To understand neuroinflammation-related gene regulation during normal aging and in sporadic Alzheimer disease (sAD), we performed functional genomics analysis and analyzed messenger RNA (mRNA) expression by quantitative reverse transcriptionYpolymerase chain reaction of 22 genes involved in neuroinflammation-like responses in the cerebral cortex of wild-type and APP/PS1 transgenic mice. For direct comparisons, mRNA expression of 18 of the same genes was then analyzed in the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 of middle-aged human subjects lacking Alzheimer diseaseYrelated pathology and in older subjects with sAD pathology covering Stages IYII/0(A), IIIYIV/AYB, and VYVI/C of Braak and Braak classification. Modifications of cytokine and immune mediator mRNA expression were found with normal aging in wild-type mice and in middle-aged individuals and patients with early stages of sAD-related pathology; these were accompanied by increased protein expression of certain mediators in ramified microglia. In APP/PS1 mice, inflammatory changes coincided with β-amyloid (Aβ) deposition; increased levels of soluble oligomers paralleled the modified mRNA expression of cytokines and mediators in wild-type mice. In patients with sAD, regulation was stage- and region-dependent and not merely acceleration and exacerbation of mRNA regulation with aging. Gene regulation at first stages of AD was not related to hyperphosphorylated tau deposition in neurofibrillary tangles, Aβ plaque burden, concentration of Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), or fibrillar Aβ linked to membranes but rather to increased levels of soluble oligomers. Thus, species differences and regionand stage-dependent inflammatory responses in sAD, particularly at the initial stages, indicate the need to identify new anti-inflammatory compounds with specific molecular therapeutic targets. © 2015 by the American Association of Neuropathologists, Inc.

Ninerola-Baizan A.,University of Barcelona | Ninerola-Baizan A.,Research Center Biomedica En Red Of Bioingenieria | Rojas S.,Thrombotargets Europe S.L. | Bonastre M.,Institute dInvestigacions Biomediques August Pi i Sunyer | And 11 more authors.
Contrast Media and Molecular Imaging | Year: 2015

The 6-hydroxydopamine (6-OHDA) rodent model of Parkinson's disease (PD) has been used to evaluate the nigrostriatal pathway. The aim of this work was to explore the relationship between the degree of 6-OHDA-induced dopaminergic degeneration and [123I]FP-CIT binding using single photon emission computed tomography (SPECT). Fourteen rats received a 6-OHDA injection (4 or 8μg) into the left medial forebrain bundle. After 3weeks, magnetic resonance imaging and scans with a small-animal SPECT system were performed. Finally, the nigrostriatal lesion was assessed by immunohistochemical analysis. Immunohistochemical analysis confirmed two levels of dopaminergic degeneration. Lesions induced by 6-OHDA diminished the ipsilateral [123I]FP-CIT binding by 61 and 76%, respectively. The decrease in tracer uptake between control and lesioned animals was statistically significant, as was the difference between the two 6-OHDA lesioned groups. Results concluded that [123I]FP-CIT SPECT is a useful technique to discriminate the degree of dopaminergic degeneration in a rat model of PD. © 2014 John Wiley & Sons, Ltd.

Ansoleaga B.,Bellvitge University Hospital | Garcia-Esparcia P.,Bellvitge University Hospital | Llorens F.,Bellvitge University Hospital | Llorens F.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | And 5 more authors.
Neuroscience | Year: 2013

Recently, we have shown the expression of novel chemoreceptors corresponding to the olfactory receptor (OR) and taste receptor (TASR) families in the human brain. We have also shown dysregulation of ORs and TASRs in the cerebral cortex in Parkinson's disease. The present study demonstrates the presence of OR mRNA and mRNA of obligated downstream components of OR signaling adenylyl cyclase 3 (ADYLC3) and olfactory G protein (Gnal) in the cerebral cortex of the mouse. Dysregulation of selected ORs and TASRs has been found in the entorhinal cortex and frontal cortex in Alzheimer's disease (AD) in a gradient compatible with Braak and Braak staging; frontal cortex in terminal stages of Progressive Supranuclear Palsy; and frontal cortex and cerebellum in Creutzfeldt-Jakob disease subtypes methionine/methionine at codón 129 of PRNP (MM1) and valine/valine at codón 129 of PRNP (VV2). Altered OR, ADYLC3 and Gnal mRNA expression with disease progression has also been found in APP/PS1 transgenic mice, used as a model of AD. The function of these orphan receptors is not known, but probably related to cell signaling pathways responding to unidentified ligands.Variability in the drift, either down- or up-regulation, of dysregulated genes, suggests that central ORs and TASRs are vulnerable to variegated neurodegenerative diseases with cortical involvement, and that altered expression of ORs and TASRs is not a mere reflection of neuronal loss but rather a modulated pathological response. © 2013 IBRO.

Medina M.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | Medina M.,Queen Sofia Alzheimer Research Center | Avila J.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas
Expert Review of Neurotherapeutics | Year: 2014

Tau is a brain microtubule-associated protein that regulates microtubule structure and function. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders collectively referred to as tauopathies, the most common of which is Alzheimer's disease. Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have unveiled novel important tau cellular functions that may also play a pivotal role in pathogenesis and render novel targets for therapeutic intervention. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, especially phosphorylation, which has significant implications for the development of novel therapeutic approaches in a number of neurodegenerative disorders. © Informa UK, Ltd.

Ardite E.,University Pompeu Fabra | Ardite E.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | Perdiguero E.,University Pompeu Fabra | Perdiguero E.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | And 9 more authors.
Journal of Cell Biology | Year: 2012

Disruption of skeletal muscle homeostasis by substitution with fibrotic tissue constitutes the principal cause of death in Duchenne muscular dystrophy (DMD) patients, yet the implicated fibrogenic mechanisms remain poorly understood. This study identifies the extracellular PAI-1/urokinase-type plasminogen activator (uPA) balance as an important regulator of microribonucleic acid (miR)-21 biogenesis, controlling age-associated muscle fibrosis and dystrophy progression. Genetic loss of PAI-1 in mdx dystrophic mice anticipated muscle fibrosis through these sequential mechanisms: the alteration of collagen metabolism by uPA-mediated proteolytic processing of transforming growth factor (TGF)-β in muscle fibroblasts and the activation of miR-21 expression, which inhibited phosphatase and tensin homologue and enhanced AKT signaling, thus endowing TGF-β with a remarkable cell proliferation-promoting potential. Ageassociated fibrogenesis and muscle deterioration in mdx mice, as well as exacerbated dystrophy in young PAI-1 -/-mdx mice, could be reversed by miR-21 or uPA-selective interference, whereas forced miR-21 overexpression aggravated disease severity. The PAI-1-miR-21 fibrogenic axis also appeared dysregulated in muscle of DMD patients, providing a basis for effectively targeting fibrosis and muscular dystrophies in currently untreatable individuals. © 2012 Ardite et al.

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