114 results on '"Hamdane M"'
Search Results
2. A2A adenosine receptor deletion is protective in a mouse model of Tauopathy
- Author
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Laurent, C, Burnouf, S, Ferry, B, Batalha, V L, Coelho, J E, Baqi, Y, Malik, E, Mariciniak, E, Parrot, S, Van der Jeugd, A, Faivre, E, Flaten, V, Ledent, C, DʼHooge, R, Sergeant, N, Hamdane, M, Humez, S, Müller, C E, Lopes, L V, Buée, L, and Blum, D
- Published
- 2016
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3. Le retard diagnostique dans les tumeurs du système nerveux central de l’enfant
- Author
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Hamdane, M. M., Bougrine, F., Ben Ammar, M., Msekni, I., Yedes, M., and Bouziani, A.
- Published
- 2012
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- View/download PDF
4. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology
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Chapuis, J, Hansmannel, F, Gistelinck, M, Mounier, A, Van Cauwenberghe, C, Kolen, K V, Geller, F, Sottejeau, Y, Harold, D, Dourlen, P, Grenier-Boley, B, Kamatani, Y, Delepine, B, Demiautte, F, Zelenika, D, Zommer, N, Hamdane, M, Bellenguez, C, Dartigues, J-F, Hauw, J-J, Letronne, F, Ayral, A-M, Sleegers, K, Schellens, A, Broeck, L V, Engelborghs, S, De Deyn, P P, Vandenberghe, R, OʼDonovan, M, Owen, M, Epelbaum, J, Mercken, M, Karran, E, Bantscheff, M, Drewes, G, Joberty, G, Campion, D, Octave, J-N, Berr, C, Lathrop, M, Callaerts, P, Mann, D, Williams, J, Buée, L, Dewachter, I, Van Broeckhoven, C, Amouyel, P, Moechars, D, Dermaut, B, and Lambert, J-C
- Published
- 2013
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5. Cellular contaminants of adeno-associated virus vector stocks can enhance transduction
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Tenenbaum, L, Hamdane, M, Pouzet, M, Avalosse, B, Stathopoulos, A, Jurysta, F, Rosenbaum, C, Hanemann, C O, Levivier, M, and Velu, T
- Published
- 1999
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6. Loss of Medial Septum Cholinergic Neurons in THY-Tau22 Mouse Model: What Links with tau Pathology?
- Author
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Belarbi, K., Burnouf, S., Fernandez-Gomez, F.-J., Desmercières, J., Troquier, L., Brouillette, J., Tsambou, L., Grosjean, M.-E., Caillierez, R., Demeyer, D., Hamdane, M., Schindowski, K., Blum, D., and Buée, L.
- Published
- 2011
7. Erratum: A2A adenosine receptor deletion is protective in a mouse model of Tauopathy
- Author
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Laurent, C, Burnouf, S, Ferry, B, Batalha, V L, Coelho, J E, Baqi, Y, Malik, E, Mariciniak, E, Parrot, S, Van der Jeugd, A, Faivre, E, Flaten, V, Ledent, C, D'Hooge, R, Sergeant, N, Hamdane, M, Humez, S, Müller, C E, Lopes, L V, Buée, L, and Blum, D
- Published
- 2016
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- View/download PDF
8. A2A adenosine receptor deletion is protective in a mouse model of Tauopathy
- Author
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Laurent, C., Burnouf, S., Ferry, B., Batalha, Vânia, Coelho, Joana E, Baqi, Y., Malik, E., Mariciniak, E., Parrot, S., Van der Jeugd, A., Faivre, E., Flaten, V., Ledent, C., D'Hooge, R., Sergeant, N., Hamdane, M., Humez, S., Müller, C. E., Lopes, Luisa V., Buée, L., Blum, D., and Repositório da Universidade de Lisboa
- Subjects
Receptor, Adenosine A2A ,Long-Term Synaptic Depression ,Glutamic Acid ,Biologie moléculaire ,Mice, Transgenic ,tau Proteins ,Hippocampus ,Adenosine A2 Receptor Antagonists ,Tissue Culture Techniques ,Disease Models, Animal ,Tauopathies ,Alzheimer Disease ,Xanthines ,Animals ,Humans ,RNA, Messenger ,Phosphorylation ,Cognition Disorders ,Sciences cognitives ,gamma-Aminobutyric Acid ,Psychiatrie - Abstract
© 2016 Macmillan Publishers Limited All rights reserved. This work is licensed under a Creative Commons Attribution- NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/, Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies., This work was supported by grants from France Alzheimer (to DB) and LECMA/Alzheimer Forschung Initiative (to DB and CEM). DB and LVL got a Égide/Pessoa program EU exchange grant. Our laboratory is also supported by the LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), Inserm, CNRS, Université Lille 2, Lille Métropole Communauté Urbaine, Région Nord/Pas-de-Calais, FEDER, DN2M, ANR (ADONTAGE and ADORATAU, to DB) and FUI MEDIALZ. We thank the animal facility of IMPRT-IFR114 and M Besegher, I Brion, D Cappe, R Dehaynin, J Devassine, Y Lepage, C Meunier and D Taillieu for transgenic mouse production and animal care, as well as M Basquin, D Demeyer, S Eddarkaoui, H Obriot and M Schneider for support. CL holds a doctoral grant from Lille 2 University, and SB from Région Nord Pas de Calais and CHRU de Lille. VF holds a grant from Région Nord-Pas-de-Calais and Inserm. EF holds a post-doctoral grant from Région Nord-Pas-de-Calais (DN2M). LVL is an Investigator FCT (Fundação para a Ciência e Tecnologia, Portugal).
- Published
- 2016
9. Erratum: A2A adenosine receptor deletion is protective in a mouse model of Tauopathy
- Author
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Laurent, C, primary, Burnouf, S, additional, Ferry, B, additional, Batalha, V L, additional, Coelho, J E, additional, Baqi, Y, additional, Malik, E, additional, Mariciniak, E, additional, Parrot, S, additional, Van der Jeugd, A, additional, Faivre, E, additional, Flaten, V, additional, Ledent, C, additional, D'Hooge, R, additional, Sergeant, N, additional, Hamdane, M, additional, Humez, S, additional, Müller, C E, additional, Lopes, L V, additional, Buée, L, additional, and Blum, D, additional
- Published
- 2015
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10. A2A adenosine receptor deletion is protective in a mouse model of Tauopathy
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Laurent, C, primary, Burnouf, S, additional, Ferry, B, additional, Batalha, V L, additional, Coelho, J E, additional, Baqi, Y, additional, Malik, E, additional, Mariciniak, E, additional, Parrot, S, additional, Van der Jeugd, A, additional, Faivre, E, additional, Flaten, V, additional, Ledent, C, additional, D'Hooge, R, additional, Sergeant, N, additional, Hamdane, M, additional, Humez, S, additional, Müller, C E, additional, Lopes, L V, additional, Buée, L, additional, and Blum, D, additional
- Published
- 2014
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11. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.
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UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Chapuis, J, Hansmannel, F, Gistelinck, M, Mounier, A, Van Cauwenberghe, C, Kolen, K V, Geller, F, Sottejeau, Y, Harold, D, Dourlen, P, Grenier-Boley, B, Kamatani, Y, Delepine, B, Demiautte, F, Zelenika, D, Zommer, N, Hamdane, M, Bellenguez, C, Dartigues, J-F, Hauw, J-J, Letronne, F, Ayral, A-M, Sleegers, K, Schellens, A, Broeck, L V, Engelborghs, S, De Deyn, P P, Vandenberghe, R, O'Donovan, M, Owen, M, Epelbaum, J, Mercken, M, Karran, E, Bantscheff, M, Drewes, G, Joberty, G, Campion, D, Octave, Jean-Noël, Berr, C, Lathrop, M, Callaerts, P, Mann, D, Williams, J, Buée, L, Dewachter, Ilse, Van Broeckhoven, C, Amouyel, P, Moechars, D, Dermaut, B, Lambert, J-C, GERAD consortium, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Chapuis, J, Hansmannel, F, Gistelinck, M, Mounier, A, Van Cauwenberghe, C, Kolen, K V, Geller, F, Sottejeau, Y, Harold, D, Dourlen, P, Grenier-Boley, B, Kamatani, Y, Delepine, B, Demiautte, F, Zelenika, D, Zommer, N, Hamdane, M, Bellenguez, C, Dartigues, J-F, Hauw, J-J, Letronne, F, Ayral, A-M, Sleegers, K, Schellens, A, Broeck, L V, Engelborghs, S, De Deyn, P P, Vandenberghe, R, O'Donovan, M, Owen, M, Epelbaum, J, Mercken, M, Karran, E, Bantscheff, M, Drewes, G, Joberty, G, Campion, D, Octave, Jean-Noël, Berr, C, Lathrop, M, Callaerts, P, Mann, D, Williams, J, Buée, L, Dewachter, Ilse, Van Broeckhoven, C, Amouyel, P, Moechars, D, Dermaut, B, Lambert, J-C, and GERAD consortium
- Abstract
Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.
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- 2013
12. S.02.04 Physiopathological features of tauopathies and tau transgenic mice
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Buée, L., primary, Burnouf, S., additional, Troquier, L., additional, Leboucher, A., additional, Laurent, C., additional, Le Freche, H., additional, Brouillette, J., additional, Hamdane, M., additional, Sergeant, N., additional, and Blum, D., additional
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- 2010
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13. C10 Modèles expérimentaux de la pathologie Tau
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Hamdane, M., primary, Desmercières, J., additional, Burnouf, S., additional, Bouafia, H., additional, Belarbi, K., additional, Troquier, L., additional, Becque, S., additional, Demeyer, D., additional, Grosjean, M.-E., additional, Caillierez, R., additional, Barbot, B., additional, Brion, I., additional, Fernandez Gomez, F., additional, Humez, S., additional, Sergeant, N., additional, Blum, D., additional, and Buée, L., additional
- Published
- 2009
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14. P1-20 Effets de l’exercice volontaire à long terme dans un modèle de souris transgénique THY-Tau22 développant une pathologie Tau similaire à celle observée dans la maladie d’Alzheimer
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Troquier, L., primary, Burnouf, S., additional, Belarbi, K., additional, Fernandez-Gomez, F., additional, Sultan, A., additional, Grosjean, M.-E., additional, Demeyer, D., additional, Obriot, H., additional, Caillierez, R., additional, Galas, M.-C., additional, Brion, I., additional, Barbot, B., additional, Humez, S., additional, Sergeant, N., additional, Hamdane, M., additional, Blum, D., additional, and Buée, L., additional
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- 2009
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15. P1-21 Mécanismes sous jacents à l’immunothérapie anti-Tau dans la maladie d’Alzheimer
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Troquier, L., primary, Caillierez, R., additional, Kervoaze, G., additional, Grosjean, M.-E., additional, Brion, I., additional, Barbot, B., additional, Maurage, C.-A., additional, Blum, D., additional, Hamdane, M., additional, Lassalle, P., additional, Sergeant, N., additional, and Buée, L., additional
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- 2009
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16. P1-3 Effet de la déplétion en hormones stéroïdes femelles sur la pathologie Tau dans un modèle transgénique murin de Tauopathie
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Buee-Scherrer, V., primary, Lopes-Martins, K., additional, Belarbi, K., additional, Burnouf, S., additional, Fernandez-Gomez, F., additional, Caillierez, R., additional, Grosjean, M.-E., additional, Mazur, D., additional, Demeyer, D., additional, Brion, I., additional, Barbot, B., additional, Prevot, V., additional, Hamdane, M., additional, Bantubungi, K., additional, Sergeant, N., additional, Buée, L., additional, and Blum, D., additional
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- 2009
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17. The peptidyl prolyl cis/trans isomerase Pin1 downregulates the Inhibitor of Apoptosis Protein Survivin
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Dourlen, P., primary, Ando, K., additional, Hamdane, M., additional, Begard, S., additional, Buée, L., additional, and Galas, M.C., additional
- Published
- 2007
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18. C2-4 La protéine microtubulaire Tau : le ying et le yang des tauopathies
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Hamdane, M., primary, Bretteville, A., additional, Ando, K., additional, Dourlen, P., additional, Schindowski, K., additional, Kerdraon, O., additional, Bégard, S., additional, Schraen-Mashke, S., additional, Caillet-Boudin, M.L., additional, Sergeant, N., additional, Delacourte, A., additional, Galas, M.C., additional, Maurage, C.A., additional, and Buée, L., additional
- Published
- 2005
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19. Proteasome inhibition and Tau proteolysis: an unexpected regulation
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Delobel, P., primary, Leroy, O., additional, Hamdane, M., additional, Sambo, A.V., additional, Delacourte, A., additional, and Buée, L., additional
- Published
- 2004
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20. Immunolocalization of Inhibin and Activin α and βB Subunits and Expression of Corresponding Messenger RNAs in the Human Adult Testis
- Author
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Marchetti, C., primary, Hamdane, M., additional, Mitchell, V., additional, Mayo, K., additional, Devisme, L., additional, Rigot, J.M., additional, Beauvillain, J.C., additional, Hermand, E., additional, and Defossez, A., additional
- Published
- 2003
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21. Modelling Alzheimer-specific abnormal Tau phosphorylation independently of GSK3β and PKA kinase activities
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Delobel, P, primary, Flament, S, additional, Hamdane, M, additional, Delacourte, A, additional, Vilain, J.P, additional, and Buée, L, additional
- Published
- 2002
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22. A2Aadenosine receptor deletion is protective in a mouse model of Tauopathy
- Author
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Laurent, C, Burnouf, S, Ferry, B, Batalha, V L, Coelho, J E, Baqi, Y, Malik, E, Mariciniak, E, Parrot, S, Van der Jeugd, A, Faivre, E, Flaten, V, Ledent, C, D'Hooge, R, Sergeant, N, Hamdane, M, Humez, S, Müller, C E, Lopes, L V, Buée, L, and Blum, D
- Abstract
Consumption of caffeine, a non-selective adenosine A2Areceptor (A2AR) antagonist, reduces the risk of developing Alzheimer’s disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2Areceptors as important molecular targets to consider against AD and Tauopathies.
- Published
- 2016
- Full Text
- View/download PDF
23. Immunothérapie génique du cancer : bilan et perspectives.
- Author
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Leclercq, V, primary, Hamdane, M, additional, Bruyns, C, additional, Faid, L, additional, Gangji, D, additional, and Velu, T, additional
- Published
- 1999
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24. Proteasome inhibition and Tau proteolysis: an unexpected regulation
- Author
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Delobel, P., Leroy, O., Hamdane, M., Sambo, A.V., Delacourte, A., and Buée, L.
- Subjects
GEL electrophoresis ,PARKINSON'S disease ,POLYACRYLAMIDE ,NERVOUS system - Abstract
Abstract: Increasing evidence suggests that an inhibition of the proteasome, as demonstrated in Parkinson’s disease, might be involved in Alzheimer’s disease. In this disease and other Tauopathies, Tau proteins are hyperphosphorylated and aggregated within degenerating neurons. In this state, Tau is also ubiquitinated, suggesting that the proteasome might be involved in Tau proteolysis. Thus, to investigate if proteasome inhibition leads to accumulation, hyperphosphorylation and aggregation of Tau, we used neuroblastoma cells overexpressing Tau proteins. Surprisingly, we showed that the inhibition of the proteasome led to a bidirectional degradation of Tau. Following this result, the cellular mechanisms that may degrade Tau were investigated. [Copyright &y& Elsevier]
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- 2005
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25. Abnormal Tau phosphorylation of the Alzheimer-type also occurs during mitosis.
- Author
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Delobel, P., Flament, S., Hamdane, M., Mailliot, C., Sambo, A-V., Bégard, S., Sergeant, N., Delacourte, A., Vilain, J-P., and Buée, L.
- Subjects
ALZHEIMER'S disease ,MITOSIS ,PHOSPHORYLATION - Abstract
In Alzheimer's disease, neurofibrillary degeneration results from the aggregation of abnormally phosphorylated Tau proteins into filaments and it may be related to the reactivation of mitotic mechanisms. In order to investigate the link between Tau phosphorylation and mitosis, Xenopus laevis oocytes in which most of the M-phase regulators have been discovered were used as a cell model. The human Tau isoform htau412 (2+3–10+) was microinjected into prophase I oocytes that were then stimulated by progesterone that activate cyclin-dependent kinase pathways. Hyperphosphorylation of the Tau isoform, which is characterized by a decrease of its electrophoretic mobility and its labelling by a number of phosphorylation-dependent antibodies, was observed at the time of germinal vesicle breakdown. Surprisingly, Tau immunoreactivity, considered as typical of Alzheimer's pathology (AT100 and phospho-Ser422), was observed in meiosis II. Because meiosis II is considered as a mitosis-like phase, we investigated if our observation was also relevant to a neurone-like model. Abnormal Tau phosphorylation was detected in mitotic human neuroblastoma SY5Y cells overexpressing Tau. Regarding AT100-immunoreactivity and phospho-Ser422, we suggest that phosphatase 2A inhibition and a phosphorylation combination of mitotic kinases may lead to this Alzheimer-type phosphorylation. Our results not only demonstrate the involvement of mitotic kinases in Alzheimer-type Tau phosphorylation but also indicate that Xenopus oocyte could be a useful model to identify the kinases involved in this process. [ABSTRACT FROM AUTHOR]
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- 2002
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26. Immunolocalization of Inhibin and Activin α and βBSubunits and Expression of Corresponding Messenger RNAs in the Human Adult Testis
- Author
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Marchetti, C., Hamdane, M., Mitchell, V., Mayo, K., Devisme, L., Rigot, J.M., Beauvillain, J.C., Hermand, E., and Defossez, A.
- Abstract
Inhibin B is a testicular peptide hormone that regulates FSH secretion in a negative feedback loop. Inhibin B is a dimer of an α and a βBsubunit. In adult testes, the cellular site of production is still controversial, and it was hypothesized that germ cells contribute to inhibin B production. To determine which cell types in the testes may produce inhibin B, the immunohistochemical localization of the two subunits of inhibin B were examined in adult testicular biopsies with normal spermatogenesis, spermatogenic arrest, or Sertoli cell only (SCO) tubules. Moreover, using in situ hybridization with mRNA probes, the mRNA expression patterns of inhibin α and inhibin/activin βBsubunits have been investigated. In all testes, Sertoli cells and Leydig cells showed positive immunostaining for inhibin α subunit and expressed inhibin α subunit mRNA. Using inhibin βBsubunit immunoserum on testes with normal spermatogenesis and with spermatogenic arrest, intense labeling was located in germ cells from pachytene spermatocytes to round spermatids but not in Sertoli cells. Inhibin βBsubunit mRNA expression was intense in germ cells from spermatogonia to round spermatids and in Sertoli cells in these testes. In testes with SCO, high inhibin βBsubunit mRNA labeling density was observed in both Sertoli cells and Leydig cells, whereas βBsubunit immunostaining was negative for Sertoli cells and faintly positive for Leydig cells. These results agree with the recent opinion that inhibin B in adult men is possibly a joint product of Sertoli cells and germ cells.
- Published
- 2003
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27. [Tau story: from frontotemporal dementia to other tauopathies]
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Luc BUEE, Hamdane M, Delobel P, Av, Sambo, Bégard S, Ghestem A, Sergeant N, and Delacourte A
28. Modelling of a fluidized bed immobilized enzyme reactor. Application to the hydrolysis of maltodextrins
- Author
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Hamdane, M., primary, Wilhelm, A.M., additional, and Riba, J.P., additional
- Published
- 1988
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29. Erratum: A2Aadenosine receptor deletion is protective in a mouse model of Tauopathy
- Author
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Laurent, C, Burnouf, S, Ferry, B, Batalha, V L, Coelho, J E, Baqi, Y, Malik, E, Mariciniak, E, Parrot, S, Van der Jeugd, A, Faivre, E, Flaten, V, Ledent, C, D'Hooge, R, Sergeant, N, Hamdane, M, Humez, S, Müller, C E, Lopes, L V, Buée, L, and Blum, D
- Abstract
Correction to: Molecular Psychiatry advance online publication, 2 December 2014; doi:10.1038/mp.2014.151 Following publication of this paper, the authors noticed that the eighth author’s name was misspelled. The author’s name should have been listed as E Marciniak.
- Published
- 2016
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30. Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice.
- Author
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Gomez-Murcia V, Launay A, Carvalho K, Burgard A, Meriaux C, Caillierez R, Eddarkaoui S, Kilinc D, Siedlecki-Wullich D, Besegher M, Bégard S, Thiroux B, Jung M, Nebie O, Wisztorski M, Déglon N, Montmasson C, Bemelmans AP, Hamdane M, Lebouvier T, Vieau D, Fournier I, Buee L, Lévi S, Lopes LV, Boutillier AL, Faivre E, and Blum D
- Subjects
- Animals, Mice, Hippocampus metabolism, Hippocampus pathology, Presenilin-1 genetics, Disease Models, Animal, Plaque, Amyloid pathology, Plaque, Amyloid metabolism, Male, Mice, Inbred C57BL, Memory Disorders metabolism, Memory Disorders genetics, Memory Disorders pathology, Receptor, Adenosine A2A metabolism, Receptor, Adenosine A2A genetics, Synapses metabolism, Synapses pathology, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Mice, Transgenic, Neurons metabolism, Neurons pathology, Alzheimer Disease metabolism, Alzheimer Disease pathology, Alzheimer Disease genetics
- Abstract
Early pathological upregulation of adenosine A2A receptors (A2ARs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A2AR as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2024
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31. Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey.
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da Costa PJ, Hamdane M, Buée L, and Martin F
- Abstract
Tau proteins are known to be mainly involved in regulation of microtubule dynamics. Besides this function, which is critical for axonal transport and signal transduction, tau proteins also have other roles in neurons. Moreover, tau proteins are turned into aggregates and consequently trigger many neurodegenerative diseases termed tauopathies, of which Alzheimer's disease (AD) is the figurehead. Such pathological aggregation processes are critical for the onset of these diseases. Among the various causes of tau protein pathogenicity, abnormal tau mRNA metabolism, expression and dysregulation of tau post-translational modifications are critical steps. Moreover, the relevance of tau function to general mRNA metabolism has been highlighted recently in tauopathies. In this review, we mainly focus on how mRNA metabolism impacts the onset and development of tauopathies. Thus, we intend to portray how mRNA metabolism of, or mediated by, tau is associated with neurodegenerative diseases.
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- 2022
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32. Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor.
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Carvalho K, Faivre E, Pietrowski MJ, Marques X, Gomez-Murcia V, Deleau A, Huin V, Hansen JN, Kozlov S, Danis C, Temido-Ferreira M, Coelho JE, Mériaux C, Eddarkaoui S, Gras SL, Dumoulin M, Cellai L, Landrieu I, Chern Y, Hamdane M, Buée L, Boutillier AL, Levi S, Halle A, Lopes LV, and Blum D
- Subjects
- Animals, Autopsy, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration metabolism, Hippocampus metabolism, Hippocampus pathology, Humans, Memory Disorders etiology, Memory Disorders psychology, Mice, Mice, Transgenic, Mutation, Spatial Learning, Tauopathies psychology, tau Proteins genetics, Complement C1q metabolism, Neurons metabolism, Receptor, Adenosine A2A genetics, Receptor, Adenosine A2A metabolism, Synapses pathology, Tauopathies genetics, Tauopathies pathology
- Abstract
Accumulating data support the role of tau pathology in cognitive decline in ageing and Alzheimer's disease, but underlying mechanisms remain ill-defined. Interestingly, ageing and Alzheimer's disease have been associated with an abnormal upregulation of adenosine A2A receptor (A2AR), a fine tuner of synaptic plasticity. However, the link between A2AR signalling and tau pathology has remained largely unexplored. In the present study, we report for the first time a significant upregulation of A2AR in patients suffering from frontotemporal lobar degeneration with the MAPT P301L mutation. To model these alterations, we induced neuronal A2AR upregulation in a tauopathy mouse model (THY-Tau22) using a new conditional strain allowing forebrain overexpression of the receptor. We found that neuronal A2AR upregulation increases tau hyperphosphorylation, potentiating the onset of tau-induced memory deficits. This detrimental effect was linked to a singular microglial signature as revealed by RNA sequencing analysis. In particular, we found that A2AR overexpression in THY-Tau22 mice led to the hippocampal upregulation of C1q complement protein-also observed in patients with frontotemporal lobar degeneration-and correlated with the loss of glutamatergic synapses, likely underlying the observed memory deficits. These data reveal a key impact of overactive neuronal A2AR in the onset of synaptic loss in tauopathies, paving the way for new therapeutic approaches., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2019
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33. New piperazine multi-effect drugs prevent neurofibrillary degeneration and amyloid deposition, and preserve memory in animal models of Alzheimer's disease.
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Sergeant N, Vingtdeux V, Eddarkaoui S, Gay M, Evrard C, Le Fur N, Laurent C, Caillierez R, Obriot H, Larchanché PE, Farce A, Coevoet M, Carato P, Kouach M, Descat A, Dallemagne P, Buée-Scherrer V, Blum D, Hamdane M, Buée L, and Melnyk P
- Subjects
- Animals, Cell Line, Disease Models, Animal, Humans, Memory drug effects, Mice, Inbred C57BL, Mice, Transgenic, Neurons drug effects, Plaque, Amyloid pathology, Alzheimer Disease pathology, Brain drug effects, Nerve Degeneration pathology, Neuroprotective Agents pharmacology, Piperazines pharmacology
- Abstract
Alzheimer's Disease is a devastating dementing disease involving amyloid deposits, neurofibrillary tangles, progressive and irreversible cognitive impairment. Today, only symptomatic drugs are available and therapeutic treatments, possibly acting at a multiscale level, are thus urgently needed. To that purpose, we designed multi-effects compounds by synthesizing drug candidates derived by substituting a novel N,N'-disubstituted piperazine anti-amyloid scaffold and adding acetylcholinesterase inhibition property. Two compounds were synthesized and evaluated. The most promising hybrid molecule reduces both the amyloid pathology and the Tau pathology as well as the memory impairments in a preclinical model of Alzheimer's disease. In vitro also, the compound reduces the phosphorylation of Tau and inhibits the release of Aβ peptides while preserving the processing of other metabolites of the amyloid precursor protein. We synthetized and tested the first drug capable of ameliorating both the amyloid and Tau pathology in animal models of AD as well as preventing the major brain lesions and associated memory impairments. This work paves the way for future compound medicines against both Alzheimer's-related brain lesions development and the associated cognitive impairments., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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34. Brain insulin response and peripheral metabolic changes in a Tau transgenic mouse model.
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Leboucher A, Ahmed T, Caron E, Tailleux A, Raison S, Joly-Amado A, Marciniak E, Carvalho K, Hamdane M, Bantubungi K, Lancel S, Eddarkaoui S, Caillierez R, Vallez E, Staels B, Vieau D, Balschun D, Buee L, and Blum D
- Subjects
- Animals, Insulin Resistance physiology, Mice, Mice, Inbred C57BL, Mice, Transgenic, tau Proteins genetics, Brain metabolism, Insulin metabolism, Tauopathies metabolism, tau Proteins metabolism
- Abstract
Accumulation of hyper-phosphorylated and aggregated Tau proteins is a neuropathological hallmark of Alzheimer's Disease (AD) and Tauopathies. AD patient brains also exhibit insulin resistance. Whereas, under normal physiological conditions insulin signaling in the brain mediates plasticity and memory formation, it can also regulate peripheral energy homeostasis. Thus, in AD, brain insulin resistance affects both cognitive and metabolic changes described in these patients. While a role of Aβ oligomers and APOE4 towards the development of brain insulin resistance emerged, contribution of Tau pathology has been largely overlooked. Our recent data demonstrated that one of the physiological function of Tau is to sustain brain insulin signaling. We postulated that under pathological conditions, hyper-phosphorylated/aggregated Tau is likely to lose this function and to favor the development of brain insulin resistance. This hypothesis was substantiated by observations from patient brains with pure Tauopathies. To address the potential link between Tau pathology and brain insulin resistance, we have evaluated the brain response to insulin in a transgenic mouse model of AD-like Tau pathology (THY-Tau22). Using electrophysiological and biochemical evaluations, we surprisingly observed that, at a time when Tau pathology and cognitive deficits are overt and obvious, the hippocampus of THY-Tau22 mice exhibits enhanced response to insulin. In addition, we demonstrated that the ability of i.c.v. insulin to promote body weight loss is enhanced in THY-Tau22 mice. In line with this, THY-Tau22 mice exhibited a lower body weight gain, hypoleptinemia and hypoinsulinemia and finally a metabolic resistance to high-fat diet. The present data highlight that the brain of transgenic Tau mice exhibit enhanced brain response to insulin. Whether these observations are ascribed to the development of Tau pathology, and therefore relevant to human Tauopathies, or unexpectedly results from the Tau transgene overexpression is debatable and discussed., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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35. Tau deletion promotes brain insulin resistance.
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Marciniak E, Leboucher A, Caron E, Ahmed T, Tailleux A, Dumont J, Issad T, Gerhardt E, Pagesy P, Vileno M, Bournonville C, Hamdane M, Bantubungi K, Lancel S, Demeyer D, Eddarkaoui S, Vallez E, Vieau D, Humez S, Faivre E, Grenier-Boley B, Outeiro TF, Staels B, Amouyel P, Balschun D, Buee L, and Blum D
- Subjects
- Animals, Brain physiology, Cognitive Dysfunction etiology, Haplotypes, Hippocampus physiology, Humans, Insulin physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Brain metabolism, Insulin Resistance, tau Proteins physiology
- Abstract
The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients., (© 2017 Marciniak et al.)
- Published
- 2017
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36. The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function.
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Batalha VL, Ferreira DG, Coelho JE, Valadas JS, Gomes R, Temido-Ferreira M, Shmidt T, Baqi Y, Buée L, Müller CE, Hamdane M, Outeiro TF, Bader M, Meijsing SH, Sadri-Vakili G, Blum D, and Lopes LV
- Subjects
- Aging metabolism, Animals, Caffeine metabolism, Cell Nucleus metabolism, Cognitive Dysfunction metabolism, Corticosterone metabolism, Humans, Hypothalamo-Hypophyseal System metabolism, Hypothalamo-Hypophyseal System physiopathology, Male, Mice, Transgenic, Models, Animal, Neuronal Plasticity, Pituitary-Adrenal System metabolism, Pituitary-Adrenal System physiopathology, Rats, Aging physiology, Cognitive Dysfunction genetics, Receptor, Adenosine A2A genetics, Receptor, Adenosine A2A metabolism, Receptors, Glucocorticoid metabolism
- Abstract
Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer's disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer's and age-related cognitive impairments may rely on its ability to modulate GR actions.
- Published
- 2016
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37. The FK506-binding protein FKBP52 in vitro induces aggregation of truncated Tau forms with prion-like behavior.
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Giustiniani J, Guillemeau K, Dounane O, Sardin E, Huvent I, Schmitt A, Hamdane M, Buée L, Landrieu I, Lippens G, Baulieu EE, and Chambraud B
- Subjects
- Alzheimer Disease metabolism, Animals, Brain metabolism, Cell Line, Tumor, Humans, Male, Microtubules metabolism, Rats, Rats, Sprague-Dawley, Tauopathies metabolism, Prions metabolism, Protein Binding physiology, Tacrolimus Binding Proteins metabolism, tau Proteins metabolism
- Abstract
Tauopathies, including Alzheimer's disease (AD), are neurodegenerative diseases associated with the pathologic aggregation of human brain Tau protein. Neuronal Tau is involved in microtubule (MT) formation and stabilization. We showed previously that the immunophilin FK506-binding protein of MW ∼52 kDa (FKBP52) interferes with this function of full-length Tau and provokes aggregation of a disease-related mutant of Tau. To dissect the molecular interaction between recombinant human FKBP52 and Tau, here, we study the effect of FKBP52 on a functional Tau fragment (Tau-F4, Ser(208)-Ser(324)) containing part of the proline- rich region and MT-binding repeats. Therefore, we perform MT assembly and light-scattering assays, blue native PAGE analysis, electron microscopy, and Tau seeding experiments in SH-SY5Y human neuroblastoma cells. We show that FKBP52 (6 µM) prevents MT formation generated by Tau-F4 (5 µM) and induces Tau-F4 oligomerization and aggregation. Electron microscopy analyses show granular oligomers and filaments of Tau-F4 after short-time FKBP52 incubation. We demonstrate that the terminal parts of Tau interfere with the effects of FKBP52. Finally, we find that FKBP52-induced Tau-F4 oligomers cannot only generate in vitro, direct conformational changes in full-length Tau and that their uptake into neuronal cells can equally lead to aggregation of wild-type endogenous Tau. This suggests a potential prion-like property of these particular Tau-F4 aggregates. Collectively, our results strengthen the hypothesis of FKBP52 involvement in the Tau pathogenicity process., (© FASEB.)
- Published
- 2015
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38. Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms.
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Derisbourg M, Leghay C, Chiappetta G, Fernandez-Gomez FJ, Laurent C, Demeyer D, Carrier S, Buée-Scherrer V, Blum D, Vinh J, Sergeant N, Verdier Y, Buée L, and Hamdane M
- Subjects
- Acetylation, Alzheimer Disease genetics, Brain pathology, Cell Line, Humans, Nerve Degeneration metabolism, Phosphorylation, Protein Binding genetics, Protein Processing, Post-Translational, Proteomics, tau Proteins metabolism, Alzheimer Disease pathology, Microtubules physiology, Tubulin metabolism, tau Proteins genetics
- Abstract
Tau is a central player in Alzheimer's disease (AD) and related Tauopathies, where it is found as aggregates in degenerating neurons. Abnormal post-translational modifications, such as truncation, are likely involved in the pathological process. A major step forward in understanding the role of Tau truncation would be to identify the precise cleavage sites of the several truncated Tau fragments that are observed until now in AD brains, especially those truncated at the N-terminus, which are less characterized than those truncated at the C-terminus. Here, we optimized a proteomics approach and succeeded in identifying a number of new N-terminally truncated Tau species from the human brain. We initiated cell-based functional studies by analyzing the biochemical characteristics of two N-terminally truncated Tau species starting at residues Met11 and Gln124 respectively. Our results show, interestingly, that the Gln124-Tau fragment displays a stronger ability to bind and stabilize microtubules, suggesting that the Tau N-terminal domain could play a direct role in the regulation of microtubule stabilization. Future studies based on our new N-terminally truncated-Tau species should improve our knowledge of the role of truncation in Tau biology as well as in the AD pathological process.
- Published
- 2015
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39. Chloroquine and chloroquinoline derivatives as models for the design of modulators of amyloid Peptide precursor metabolism.
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Melnyk P, Vingtdeux V, Burlet S, Eddarkaoui S, Grosjean ME, Larchanché PE, Hochart G, Sergheraert C, Estrella C, Barrier M, Poix V, Plancq P, Lannoo C, Hamdane M, Delacourte A, Verwaerde P, Buée L, and Sergeant N
- Subjects
- Amyloid beta-Peptides metabolism, Animals, Blotting, Western, Cell Death drug effects, Cell Line, Tumor, Chloroquine chemistry, Chloroquine pharmacology, Drug Design, Female, Frontal Lobe drug effects, Frontal Lobe metabolism, Hippocampus drug effects, Hippocampus metabolism, Humans, Mice, Inbred C57BL, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Neuroprotective Agents pharmacology, Peptide Fragments metabolism, Protein Stability drug effects, Quinolines pharmacology, Water chemistry, Amyloid beta-Protein Precursor metabolism, Chloroquine analogs & derivatives, Neuroprotective Agents chemistry, Quinolines chemistry
- Abstract
The amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD). Preventing deregulated APP processing by inhibiting amyloidogenic processing of carboxy-terminal fragments (APP-CTFs), and reducing the toxic effect of amyloid beta (Aβ) peptides remain an effective therapeutic strategy. We report the design of piperazine-containing compounds derived from chloroquine structure and evaluation of their effects on APP metabolism and ability to modulate the processing of APP-CTF and the production of Aβ peptide. Compounds which retained alkaline properties and high affinity for acidic cell compartments were the most effective. The present study demonstrates that (1) the amino side chain of chloroquine can be efficiently substituted by a bis(alkylamino)piperazine chain, (2) the quinoline nucleus can be replaced by a benzyl or a benzimidazole moiety, and (3) pharmacomodulation of the chemical structure allows the redirection of APP metabolism toward a decrease of Aβ peptide release, and increased stability of APP-CTFs and amyloid intracellular fragment. Moreover, the benzimidazole compound 29 increases APP-CTFs in vivo and shows promising activity by the oral route. Together, this family of compounds retains a lysosomotropic activity which inhibits lysosome-related Aβ production, and is likely to be beneficial for therapeutic applications in AD.
- Published
- 2015
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40. Beneficial effects of caffeine in a transgenic model of Alzheimer's disease-like tau pathology.
- Author
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Laurent C, Eddarkaoui S, Derisbourg M, Leboucher A, Demeyer D, Carrier S, Schneider M, Hamdane M, Müller CE, Buée L, and Blum D
- Subjects
- Alzheimer Disease pathology, Animals, Caffeine metabolism, Caffeine pharmacology, Disease Models, Animal, Hippocampus pathology, Male, Memory Disorders prevention & control, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation drug effects, Proteolysis drug effects, Alzheimer Disease metabolism, Alzheimer Disease prevention & control, Caffeine administration & dosage, Hippocampus metabolism, tau Proteins metabolism
- Abstract
Tau pathology found in Alzheimer's disease (AD) is crucial in cognitive decline. Epidemiologic evidences support that habitual caffeine intake prevents memory decline during aging and reduces the risk to develop Alzheimer's disease. So far, experimental studies addressed the impact of caffeine in models mimicking the amyloid pathology of AD. However, in vivo effects of caffeine in a model of AD-like tauopathy remain unknown. Here, we evaluated effects of chronic caffeine intake (0.3 g/L through drinking water), given at an early pathologic stage, in the THY-Tau22 transgenic mouse model of progressive AD-like tau pathology. We found that chronic caffeine intake prevents from the development of spatial memory deficits in tau mice. Improved memory was associated with reduced hippocampal tau phosphorylation and proteolytic fragments. Moreover, caffeine treatment mitigated several proinflammatory and oxidative stress markers found upregulated in the hippocampus of THY-Tau22 animals. Together, our data support that moderate caffeine intake is beneficial in a model of AD-like tau pathology, paving the way for future clinical evaluation in AD patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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41. Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis.
- Author
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Charton J, Gauriot M, Guo Q, Hennuyer N, Marechal X, Dumont J, Hamdane M, Pottiez V, Landry V, Sperandio O, Flipo M, Buee L, Staels B, Leroux F, Tang WJ, Deprez B, and Deprez-Poulain R
- Subjects
- Acetates chemical synthesis, Acetates chemistry, Amyloid beta-Peptides metabolism, Dose-Response Relationship, Drug, Humans, Hydrolysis, Molecular Structure, Small Molecule Libraries chemical synthesis, Small Molecule Libraries chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, Acetates pharmacology, Amyloid beta-Peptides antagonists & inhibitors, Imidazoles chemistry, Insulysin metabolism, Small Molecule Libraries pharmacology
- Abstract
Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure-activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2014
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42. Consensus brain-derived protein, extraction protocol for the study of human and murine brain proteome using both 2D-DIGE and mini 2DE immunoblotting.
- Author
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Fernandez-Gomez FJ, Jumeau F, Derisbourg M, Burnouf S, Tran H, Eddarkaoui S, Obriot H, Dutoit-Lefevre V, Deramecourt V, Mitchell V, Lefranc D, Hamdane M, Blum D, Buée L, Buée-Scherrer V, and Sergeant N
- Subjects
- Animals, Brain Chemistry, Carbocyanines chemistry, Fluorescent Dyes chemistry, Humans, Mice, Nerve Tissue Proteins metabolism, Proteome metabolism, Brain metabolism, Immunoblotting methods, Nerve Tissue Proteins analysis, Proteome analysis, Two-Dimensional Difference Gel Electrophoresis methods
- Abstract
Two-dimensional gel electrophoresis (2DE) is a powerful tool to uncover proteome modifications potentially related to different physiological or pathological conditions. Basically, this technique is based on the separation of proteins according to their isoelectric point in a first step, and secondly according to their molecular weights by SDS polyacrylamide gel electrophoresis (SDS-PAGE). In this report an optimized sample preparation protocol for little amount of human post-mortem and mouse brain tissue is described. This method enables to perform both two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) and mini 2DE immunoblotting. The combination of these approaches allows one to not only find new proteins and/or protein modifications in their expression thanks to its compatibility with mass spectrometry detection, but also a new insight into markers validation. Thus, mini-2DE coupled to western blotting permits to identify and validate post-translational modifications, proteins catabolism and provides a qualitative comparison among different conditions and/or treatments. Herein, we provide a method to study components of protein aggregates found in AD and Lewy body dementia such as the amyloid-beta peptide and the alpha-synuclein. Our method can thus be adapted for the analysis of the proteome and insoluble proteins extract from human brain tissue and mice models too. In parallel, it may provide useful information for the study of molecular and cellular pathways involved in neurodegenerative diseases as well as potential novel biomarkers and therapeutic targets.
- Published
- 2014
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43. From epidemiology to pathophysiology: what about caffeine in Alzheimer's disease?
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Flaten V, Laurent C, Coelho JE, Sandau U, Batalha VL, Burnouf S, Hamdane M, Humez S, Boison D, Lopes LV, Buée L, and Blum D
- Subjects
- Animals, Humans, Receptors, Purinergic P1 metabolism, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Caffeine therapeutic use, Purinergic P1 Receptor Antagonists therapeutic use
- Abstract
AD (Alzheimer's disease) is the most prevalent form of dementia in the aged population. Definitive diagnosis of AD is based on the presence of senile plaques and neurofibrillary tangles that are identified in post-mortem brain specimens. A third pathological component is inflammation. AD results from multiple genetic and environmental risk factors. Among other factors, epidemiological studies report beneficial effects of caffeine, a non-selective antagonist of adenosine receptors. In the present review, we discuss the impact of caffeine and the adenosinergic system in AD pathology as well as consequences in terms of pathology and therapeutics.
- Published
- 2014
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44. MUC1-C nuclear localization drives invasiveness of renal cancer cells through a sheddase/gamma secretase dependent pathway.
- Author
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Bouillez A, Gnemmi V, Gaudelot K, Hémon B, Ringot B, Pottier N, Glowacki F, Butruille C, Cauffiez C, Hamdane M, Sergeant N, Van Seuningen I, Leroy X, Aubert S, and Perrais M
- Subjects
- Animals, Cell Line, Tumor, Cell Nucleus metabolism, Disease Progression, Heterografts, Humans, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Mice, Mice, SCID, Mucin-1 genetics, Protein Subunits, Signal Transduction, Transfection, Amyloid Precursor Protein Secretases metabolism, Kidney Neoplasms metabolism, Mucin-1 metabolism
- Abstract
MUC1 is a membrane-anchored mucin and its cytoplasmic tail (CT) can interact with many signaling pathways and act as a co-transcription factor to activate genes involved in tumor progression and metastasis. MUC1 is overexpressed in renal cell carcinoma with correlation to prognosis and has been implicated in the hypoxic pathway, the main renal carcinogenetic pathway. In this context, we assessed the effects of MUC1 overexpression on renal cancer cells properties. Using shRNA strategy and/or different MUC1 constructs, we found that MUC1-extracellular domain and MUC1-CT are involved in increase of migration, cell viability, resistance to anoikis and in decrease of cell aggregation in cancer cells. Invasiveness depends only on MUC1-CT. Then, by using siRNA strategy and/or pharmacological inhibitors or peptides, we showed that sheddases ADAM10, ADAM17 and gamma-secretase are necessary for MUC1 C-terminal subunit (MUC1-C) nuclear location and in increase of invasion property. Finally, MUC1 overexpression increases ADAM10/17 protein expression suggesting a positive regulatory loop. In conclusion, we report that MUC1 acts in renal cancer progression and MUC1-C nuclear localization drives invasiveness of cancer cells through a sheddase/gamma secretase dependent pathway. MUC1 appears as a therapeutic target by blocking MUC1 cleavage or nuclear translocation by using pharmacological approach and peptide strategies.
- Published
- 2014
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45. Detrimental effects of diet-induced obesity on τ pathology are independent of insulin resistance in τ transgenic mice.
- Author
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Leboucher A, Laurent C, Fernandez-Gomez FJ, Burnouf S, Troquier L, Eddarkaoui S, Demeyer D, Caillierez R, Zommer N, Vallez E, Bantubungi K, Breton C, Pigny P, Buée-Scherrer V, Staels B, Hamdane M, Tailleux A, Buée L, and Blum D
- Subjects
- Animals, Behavior, Animal, Hippocampus pathology, Insulin Receptor Substrate Proteins biosynthesis, Insulin Receptor Substrate Proteins genetics, Insulin Receptor Substrate Proteins metabolism, Learning Disabilities etiology, Male, Memory Disorders etiology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins biosynthesis, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Obesity etiology, Obesity pathology, Obesity physiopathology, Phosphorylation, Protein Processing, Post-Translational, Random Allocation, Signal Transduction, Spatial Behavior, Tauopathies etiology, Tauopathies pathology, Tauopathies physiopathology, Up-Regulation, tau Proteins genetics, Diet, High-Fat adverse effects, Hippocampus metabolism, Insulin Resistance, Obesity metabolism, Tauopathies metabolism, tau Proteins metabolism
- Abstract
The τ pathology found in Alzheimer disease (AD) is crucial in cognitive decline. Midlife development of obesity, a major risk factor of insulin resistance and type 2 diabetes, increases the risk of dementia and AD later in life. The impact of obesity on AD risk has been suggested to be related to central insulin resistance, secondary to peripheral insulin resistance. The effects of diet-induced obesity (DIO) on τ pathology remain unknown. In this study, we evaluated effects of a high-fat diet, given at an early pathological stage, in the THY-Tau22 transgenic mouse model of progressive AD-like τ pathology. We found that early and progressive obesity potentiated spatial learning deficits as well as hippocampal τ pathology at a later stage. Surprisingly, THY-Tau22 mice did not exhibit peripheral insulin resistance. Further, pathological worsening occurred while hippocampal insulin signaling was upregulated. Together, our data demonstrate that DIO worsens τ phosphorylation and learning abilities in τ transgenic mice independently from peripheral/central insulin resistance.
- Published
- 2013
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46. Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.
- Author
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Ando K, Dourlen P, Sambo AV, Bretteville A, Bélarbi K, Vingtdeux V, Eddarkaoui S, Drobecq H, Ghestem A, Bégard S, Demey-Thomas E, Melnyk P, Smet C, Lippens G, Maurage CA, Caillet-Boudin ML, Verdier Y, Vinh J, Landrieu I, Galas MC, Blum D, Hamdane M, Sergeant N, and Buée L
- Subjects
- Acetylation, Adult, Aged, Aged, 80 and over, Alzheimer Disease metabolism, Animals, Biomarkers metabolism, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Transgenic, Middle Aged, NIMA-Interacting Peptidylprolyl Isomerase, Oxidation-Reduction, Phosphorylation physiology, Proline metabolism, Proteome, Serine metabolism, Brain metabolism, Peptidylprolyl Isomerase metabolism, Protein Processing, Post-Translational physiology, Tauopathies metabolism, tau Proteins metabolism
- Abstract
A prerequisite to dephosphorylation at Ser-Pro or Thr-Pro motifs is the isomerization of the imidic peptide bond preceding the proline. The peptidyl-prolyl cis/trans isomerase named Pin1 catalyzes this mechanism. Through isomerization, Pin1 regulates the function of a growing number of targets including the microtubule-associated tau protein and is supposed to be deregulated Alzheimer's disease (AD). Using proteomics, we showed that Pin1 is posttranslationally modified on more than 5 residues, comprising phosphorylation, N-acetylation, and oxidation. Although Pin1 expression remained constant, Pin1 posttranslational two-dimensional pattern was modified by tau overexpression in a tau-inducible neuroblastoma cell line, in our THY-Tau22 mouse model of tauopathy as well as in AD. Interestingly, in all of these systems, Pin1 modifications were very similar. In AD brain tissue when compared with control, Pin1 is hyperphosphorylated at serine 16 and found in the most insoluble hyperphosphorylated tau fraction of AD brain tissue. Furthermore, in all tau pathology conditions, acetylation of Pin1 may also contribute to the differences observed. In conclusion, Pin1 displays several posttranslational modifications, which are specific in tauopathies and may be useful as biomarker., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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47. NMDA receptor dysfunction contributes to impaired brain-derived neurotrophic factor-induced facilitation of hippocampal synaptic transmission in a Tau transgenic model.
- Author
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Burnouf S, Martire A, Derisbourg M, Laurent C, Belarbi K, Leboucher A, Fernandez-Gomez FJ, Troquier L, Eddarkaoui S, Grosjean ME, Demeyer D, Muhr-Tailleux A, Buisson A, Sergeant N, Hamdane M, Humez S, Popoli P, Buée L, and Blum D
- Subjects
- Alzheimer Disease genetics, Animals, Brain-Derived Neurotrophic Factor pharmacology, Disease Models, Animal, Hippocampus drug effects, Hippocampus metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Synaptic Transmission drug effects, Transgenes, tau Proteins biosynthesis, Alzheimer Disease metabolism, Brain-Derived Neurotrophic Factor metabolism, Hippocampus physiology, Receptors, N-Methyl-D-Aspartate metabolism, Synaptic Transmission physiology, tau Proteins genetics
- Abstract
While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies., (© 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)
- Published
- 2013
- Full Text
- View/download PDF
48. [A misleading tumor of the spinal cord].
- Author
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Moncef Hamdane M and Bougrine F
- Subjects
- Humans, Infant, Male, Astrocytoma pathology, Spinal Cord Neoplasms pathology
- Published
- 2013
- Full Text
- View/download PDF
49. Progressive age-related cognitive decline in tau mice.
- Author
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Van der Jeugd A, Vermaercke B, Derisbourg M, Lo AC, Hamdane M, Blum D, Buée L, and D'Hooge R
- Subjects
- Aging pathology, Animals, Cognition Disorders pathology, Disease Progression, Male, Maze Learning physiology, Mice, Mice, Transgenic, Phosphorylation genetics, Aging genetics, Aging metabolism, Cognition Disorders genetics, Cognition Disorders metabolism, tau Proteins genetics, tau Proteins metabolism
- Abstract
Age-related cognitive decline and neurodegenerative diseases are a growing challenge for society. Accumulation of tau pathology has been proposed to partially contribute to these impairments. This study provides a behavioral characterization during aging of transgenic mice bearing tau mutations. THY-Tau22 mice were evaluated at ages wherein tau neuropathology in this transgenic mouse model is low (3-4 months), moderate (6-7 months), or extensive (>9 months). Spatial memory was found to be impaired only after 9 months of age in THY-Tau22 mice, whereas non-spatial memory was affected as early as 6 months, appearing to offer an opportunity for assessing potential therapeutic agents in attenuating or preventing tauopathies through modulation of tau kinetics.
- Published
- 2013
- Full Text
- View/download PDF
50. Ewing-like adamantinoma.
- Author
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Hamdane MM, Charfi L, Driss M, Nouri H, Sellami-Dhouib R, Mrad K, Mestiri M, and Ben Romdhane K
- Subjects
- Adamantinoma therapy, Diagnosis, Differential, Humans, Male, Young Adult, Adamantinoma diagnosis, Sarcoma, Ewing diagnosis, Tibia
- Abstract
The Ewing-like variation of adamantinoma is a rare entity, leading to challenge its differential diagnosis, notably with Ewing's sarcoma. We are reporting a case of a 20-year-old male who presented with swelling in the left leg that had progressed over a 2-year period. X-rays revealed a tumour in the tibia that was intracortical, osteolytic, multilocular and invaded the soft tissues. A surgical biopsy was performed. Histopathology examination showed a tumour growth with small round cells expressing CD99. A diagnosis of Ewing's sarcoma was made. Since the patient declined surgical treatment, chemotherapy was administered. Two years later, the patient returned because the tumour had grown in size. A second biopsy was performed. Microscopic evaluation showed a tumour growth with osteofibrous and epithelial components, which expressed pankeratin and vimentin, but was negative for CD99. A diagnosis of Ewing-like adamantinoma was made., (Copyright © 2012. Published by Elsevier Masson SAS.)
- Published
- 2012
- Full Text
- View/download PDF
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